U.S. patent number RE43,039 [Application Number 12/839,260] was granted by the patent office on 2011-12-20 for dual electrode system for a continuous analyte sensor.
This patent grant is currently assigned to DexCom, Inc.. Invention is credited to James H. Brauker, Mark Brister, James R. Petisce, Peter C. Simpson.
United States Patent |
RE43,039 |
Brister , et al. |
December 20, 2011 |
**Please see images for:
( Certificate of Correction ) ** |
Dual electrode system for a continuous analyte sensor
Abstract
Disclosed herein are systems and methods for a continuous
analyte sensor, such as a continuous glucose sensor. One such
system utilizes first and second working electrodes to measure
additional analyte or non-analyte related signal. Such measurements
may provide a background and/or sensitivity measurement(s) for use
in processing sensor data and may be used to trigger events such as
digital filtering of data or suspending display of data.
Inventors: |
Brister; Mark (Encinitas,
CA), Petisce; James R. (San Clemente, CA), Simpson; Peter
C. (Encinitas, CA), Brauker; James H. (Addison, MI) |
Assignee: |
DexCom, Inc. (San Diego,
CA)
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Family
ID: |
34682162 |
Appl.
No.: |
12/839,260 |
Filed: |
July 19, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
11543734 |
Oct 4, 2006 |
7424318 |
Sep 9, 2008 |
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Current U.S.
Class: |
600/347;
600/365 |
Current CPC
Class: |
A61B
5/742 (20130101); A61B 5/7203 (20130101); A61B
5/14865 (20130101); A61B 5/14532 (20130101); A61B
5/1495 (20130101); B33Y 80/00 (20141201); B33Y
70/00 (20141201); A61B 2560/0223 (20130101) |
Current International
Class: |
A61B
5/05 (20060101) |
Field of
Search: |
;600/345-347,365 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1 077 634 |
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WO 94/22367 |
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WO |
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WO 99/56613 |
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Apr 1999 |
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WO |
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WO 99/58051 |
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Nov 1999 |
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WO |
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WO 00/33065 |
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Jun 2000 |
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WO |
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WO 01/88524 |
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Nov 2001 |
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WO |
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WO 01/88534 |
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Nov 2001 |
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WO |
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Primary Examiner: Mallari; Patricia C
Assistant Examiner: D'Angelo; Michael
Attorney, Agent or Firm: Knobbe Martens Olson & Bear
LLP
Claims
What is claimed is:
1. A glucose sensor system configured for insertion into a host for
measuring a glucose concentration in the host, the system
comprising: a sensor comprising a first working electrode and a
second working electrode, wherein the first working electrode is
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential; wherein the non-glucose related electroactive
compounds with an oxidation potential that substantially overlaps
with the first oxidation potential, and wherein the first working
electrode and the second working electrode are configured and
arranged symmetrically about a central longitudinal axis along an
overlapping length of the sensor such that the central longitudinal
axis passes through each of the working electrodes; and electronics
operably connected to the first working electrode and the second
working electrode and configured to process the first signal and
the second signal to generate a glucose concentration substantially
without signal contribution due to in vivo mechanical factors.
2. The system of claim 1, wherein at least some of the non-glucose
related electroactive compounds are substantially non-constant.
3. The system of claim 1, wherein the mechanical factors are
selected from the group consisting of macro-motion of the sensor,
micro-motion of the sensor, pressure on the sensor, and stress on
the sensor.
4. The system of claim 1, wherein the system is configured and
arranged to remove noise caused by at least one of biochemical
factors and chemical factors.
5. The system of claim 4, wherein at least one of the biochemical
factors and the chemical factors are substantially non-constant and
are selected from the group consisting of compounds with
electroactive acidic groups, compounds with electroactive amine
groups, compounds with electroactive sulfhydryl groups, urea,
lactic acid, phosphates, citrates, peroxides, amino acids, amino
acid precursors, amino acid break-down products, nitric oxide,
nitric oxide-donors, nitric oxide-precursors, electroactive species
produced during cell metabolism, electroactive species produced
during wound healing, and electroactive species that arise during
body pH changes.
6. The system of claim 4, wherein the first working electrode and
the second working electrode are configured to substantially
equally measure noise due to at least one of the biochemical
factors and the chemical factors.
7. The system of claim 1, wherein the electronics are configured to
subtract the second signal from the first signal, whereby a
differential signal comprising at least one glucose sensor data
point is determined.
8. The system of claim 7, wherein the electronics comprise a
differential amplifier configured to electronically subtract the
second signal from the first signal.
9. The system of claim 7, wherein the electronics comprise at least
one of hardware and software configured to digitally subtract the
second signal from the first signal.
10. The system of claim 1, wherein the first working electrode and
the second working electrode are configured to be impacted by
mechanical factors and biochemical species to substantially the
same extent.
11. The system of claim 10, wherein the first working electrode and
the second working electrode have a configuration selected from the
group consisting of coaxial, helically twisted, bundled, and
combinations thereof.
12. The system of claim 1, further comprising an insulator
positioned between the first working electrode and the second
working electrode.
13. The system of claim 12, wherein each of the first working
electrode, the second working electrode, and the insulator are
configured provide at least two functions selected from the group
consisting of electrical conductance, insulative property,
structural support, and diffusion barrier.
14. The system of claim 1, wherein the sensor comprises a diffusion
barrier configured to substantially block diffusion of at least one
of the analyte and the co-analyte between the first working
electrode and the second working electrode.
15. The system of claim 1, wherein the sensor further comprises an
insulator located between the first and second working electrodes,
and wherein the first working electrode, the second working
electrode, and the insulator integrally form a substantial portion
of the sensor configured for insertion in the host.
16. The system of claim 15, further comprising a reference
electrode, wherein the first working electrode, the second working
electrode, and the reference electrode integrally form a
substantial portion of the sensor configured for insertion in the
host.
17. The system of claim 1, wherein the first working electrode and
second working electrode are substantially identical.
18. The system of claim 1, wherein each of the first working
electrode and the second working electrode comprises a wire with a
diameter of from about 0.001 inches to about 0.010 inches.
19. The system of claim 1, wherein the sensor has a width of no
more than about 0.015 inches.
20. The system of claim 1, wherein the first working electrode and
the second working electrode are twisted together.
21. The system of claim 1, wherein a surface area of the first
working electrode is equal to a surface area of the second working
electrode.
22. The system of claim 1, further comprising a membrane located
over the first working electrode and second working electrode,
wherein the membrane comprises an interference domain.
23. An analyte sensor system configured for insertion into a host
for measuring an analyte in the host, the system comprising: a
continuous analyte sensor comprising a first working electrode
.Iadd.configured to generate a first signal .Iaddend.and a second
working electrode .Iadd.configured to generate a second
signal.Iaddend., wherein the first working electrode is disposed
beneath an active enzymatic portion of a membrane; wherein the
second working electrode is disposed beneath an inactive-enzymatic
or non-enzymatic portion of a membrane, and wherein the first
working electrode and the second working electrode are configured
to measure interfering biochemical species such that signal
contribution associated with the interfering biochemical species
can be substantially removed continuously for a time period,
wherein the time period is between about a few hours and about 10
days; and electronics operably connected to the first working
electrode and the second working electrode, and configured to
process the first signal and the second signal to generate
continuous sensor analyte data substantially without signal
contribution due the biochemical species for said time period.
24. The system of claim 23, wherein the signal contribution
associated with the interfering biochemical species is
substantially non-constant.
25. The system of claim 23, wherein the electronics are configured
to substantially remove noise caused by mechanical factors.
26. The system of claim 25, wherein at least one of the mechanical
factors is selected from the group consisting of macro-motion of
the sensor, micro-motion of the sensor, pressure on the sensor, and
stress on the sensor.
27. The system of claim 25, wherein the first working electrode and
the second working electrode are configured to substantially
equally measure noise due to mechanical factors, whereby noise
caused by mechanical factors can be substantially removed.
28. The system of claim 23, wherein at least one of the interfering
biochemical species is substantially non-constant and is selected
from the group consisting of compounds with electroactive acidic
groups, compounds with electroactive amine groups, compounds with
electroactive sulfhydryl groups, urea, lactic acid, phosphates,
citrates, peroxides, amino acids, amino acid precursors, amino acid
break-down products, nitric oxide, nitric oxide-donors, nitric
oxide-precursors, electroactive species produced during cell
metabolism, electroactive species produced during wound healing,
and electroactive species that arise during body pH changes.
29. The system of claim 23, further comprising at least one of a
reference electrode and a counter electrode.
30. The system of claim 29, wherein at least one of the reference
electrode and the counter electrode, together with the first
working electrode and the second working electrode, integrally form
at least a portion of the sensor.
31. The system of claim 29, wherein at least one of the reference
electrode and the counter electrode is located at a position remote
from the first working electrode and the second working
electrode.
32. The system of claim 29, wherein a surface area of at least one
of the reference electrode and the counter electrode is at least
six times a surface area of at least one of the first working
electrode and the second working electrode.
33. The system of claim 23, wherein the sensor is configured for
implantation into the host.
34. The system of claim 33, wherein the sensor is configured for
subcutaneous implantation in a tissue of the host.
35. The system of claim 33, wherein the sensor is configured for
indwelling in a blood stream of the host.
36. The system of claim 23, wherein the analyte sensor comprises a
glucose sensor, and wherein the .[.first working electrode is
configured to generate a.]. first signal .Iadd.is
.Iaddend.associated with glucose and non-glucose related
electroactive compounds, the glucose and the non-glucose related
electroactive compounds having a first oxidation potential.
37. The system of claim 36, wherein the .[.second working electrode
is configured to generate a.]. second signal .Iadd.is
.Iaddend.associated with non-glucose related electroactive
compounds with an oxidation potential that substantially overlaps
with the first oxidation potential.
38. The system of claim 37, wherein the non-glucose related
electroactive species comprises at least one species selected from
the group consisting of interfering species, non-reaction-related
hydrogen peroxide, and other electroactive species.
39. The system of claim 23, further comprising an insulator
positioned between the first working electrode and the second
working electrode.
40. The system of claim 39, wherein each of the first working
electrode, the second working electrode, and the insulator are
configured provide at least two functions selected from the group
consisting of: electrical conductance, insulative property,
structural support, and diffusion barrier.
41. The system of claim 23, wherein the sensor comprises a
diffusion barrier configured to substantially block diffusion of at
least one of an analyte and a co-analyte between the first working
electrode and the second working electrode.
42. The system of claim 23, wherein the sensor further comprises an
insulator located between the first and second working electrodes,
and wherein the first working electrode, the second working
electrode, and the insulator integrally form a substantial portion
of the sensor configured for insertion in the host.
43. The system of claim 42, further comprising a reference
electrode, wherein the first working electrode, the second working
electrode, and the reference electrode integrally form a
substantial portion of the sensor configured for insertion in the
host.
44. The system of claim 23, wherein the first working electrode and
the second working electrode are configured to be impacted by
mechanical factors to substantially the same extent.
45. The system of claim 44, wherein the first working electrode and
the second working electrode have a configuration selected from the
group consisting of coaxial, helically twisted, bundled,
symmetrical, and combination thereof.
46. The system of claim 23, wherein the first working electrode and
the second working electrode are configured and arranged with a
symmetry about the central, longitudinal axis of the sensor.
47. The system of claim 23, wherein each of the first working
electrode and the second working electrode comprises a wire with a
diameter from about 0.001 inches to about 0.010 inches.
48. The system of claim 23, wherein the sensor has a width of no
more than about 0.015 inches.
49. The system of claim 23, wherein the first working electrode and
the second working electrode are twisted together.
50. The system of claim 23, wherein a surface area of the first
working electrode is equal to a surface area of the second working
electrode.
51. The system of claim 23, wherein the membrane comprises an
interference domain located over the first and second working
electrodes.
Description
.Iadd.CROSS-REFERENCE TO RELATED APPLICATION.Iaddend.
.Iadd.This application is a reissue of U.S. Pat. No. 7,424,318,
issued Sep. 9, 2008..Iaddend.
FIELD OF THE INVENTION
The present invention relates generally to systems and methods for
measuring an analyte concentration in a host.
BACKGROUND OF THE INVENTION
Diabetes mellitus is a disorder in which the pancreas cannot create
sufficient insulin (Type 1 or insulin dependent) and/or in which
insulin is not effective (Type 2 or non-insulin dependent). In the
diabetic state, the victim suffers from high blood sugar, which may
cause an array of physiological derangements (for example, kidney
failure, skin ulcers, or bleeding into the vitreous of the eye)
associated with the deterioration of small blood vessels. A
hypoglycemic reaction (low blood sugar) may be induced by an
inadvertent overdose of insulin, or after a normal dose of insulin
or glucose-lowering agent accompanied by extraordinary exercise or
insufficient food intake.
Conventionally, a diabetic person carries a self-monitoring blood
glucose (SMBG) monitor, which typically comprises uncomfortable
finger pricking methods. Due to the lack of comfort and
convenience, a diabetic will normally only measure his or her
glucose level two to four times per day. Unfortunately, these time
intervals are so far spread apart that the diabetic will likely
find out too late, sometimes incurring dangerous side effects, of a
hyper- or hypo-glycemic condition. In fact, it is not only unlikely
that a diabetic will take a timely SMBG value, but the diabetic
will not know if their blood glucose value is going up (higher) or
down (lower) based on conventional methods, inhibiting their
ability to make educated insulin therapy decisions.
SUMMARY OF THE INVENTION
A variety of continuous glucose sensors have been developed for
detecting and/or quantifying glucose concentration in a host. These
sensors have typically required one or more blood glucose
measurements, or the like, from which to calibrate the continuous
glucose sensor to calculate the relationship between the current
output of the sensor and blood glucose measurements, to provide
meaningful values to a patient or doctor. Unfortunately, continuous
glucose sensors are conventionally also sensitive to non-glucose
related changes in the baseline current and sensitivity over time,
for example, due to changes in a host's metabolism, maturation of
the tissue at the biointerface of the sensor, interfering species
which cause a measurable increase or decrease in the signal, or the
like. Therefore, in addition to initial calibration, continuous
glucose sensors should be responsive to baseline and/or sensitivity
changes over time, which requires recalibration of the sensor.
Consequently, users of continuous glucose sensors have typically
been required to obtain numerous blood glucose measurements daily
and/or weekly in order to maintain calibration of the sensor over
time.
The preferred embodiments provide improved calibration techniques
that utilize electrode systems and signal processing that provides
measurements useful in simplifying and updating calibration that
allows the patient increased convenience (for example, by requiring
fewer reference glucose values) and confidence (for example, by
increasing accuracy of the device).
One aspect of the preferred embodiments is a method for measuring a
sensitivity change of a glucose sensor implanted in a host over a
time period comprising: 1) measuring a first signal in the host by
obtaining at least one glucose-related sensor data point, wherein
the first signal is measured at a glucose-measuring electrode
disposed beneath an enzymatic portion of a membrane system on the
sensor; 2) measuring a second signal in the host by obtaining at
least one non-glucose constant data point, wherein the second
signal is measured beneath the inactive or non-enzymatic portion of
the membrane system on the sensor; and 3) monitoring the second
signal over a time period, whereby a sensitivity change associated
with solute transport through the membrane system is measured. In
one embodiment, the second signal is indicative of a presence or
absence of a water-soluble analyte. The water-soluble analyte may
comprise urea. In one embodiment, the second signal is measured at
an oxygen-measuring electrode disposed beneath a non-enzymatic
portion of the membrane system. In one embodiment, the
glucose-measuring electrode incrementally measures oxygen, whereby
the second signal is measured. In one embodiment, the second signal
is measured at an oxygen sensor disposed beneath the membrane
system. In one embodiment, the sensitivity change is calculated as
a glucose-to-oxygen ratio, whereby an oxygen threshold is
determined that is indicative of a stability of the glucose sensor.
One embodiment further comprises filtering the first signal
responsive to the stability of the glucose sensor. One embodiment
further comprises displaying a glucose value derived from the first
signal, wherein the display is suspended depending on the stability
of the glucose sensor. One embodiment further comprises calibrating
the first signal, wherein the calibrating step is suspended when
the glucose sensor is determined to be stable. One embodiment
further comprises calibrating the glucose sensor when the
sensitivity change exceeds a preselected value. The step of
calibrating may comprise receiving a reference signal from a
reference analyte monitor, the reference signal comprising at least
one reference data point. The step of calibrating may comprise
using the sensitivity change to calibrate the glucose sensor. The
step of calibrating may be performed repeatedly at a frequency
responsive to the sensitivity change. One embodiment further
comprises determining a stability of glucose transport through the
membrane system, wherein the stability of glucose transport is
determined by measuring the sensitivity change over a time period.
One embodiment further comprises a step of prohibiting calibration
of the glucose sensor when glucose transport is determined to be
unstable. One embodiment further comprises a step of filtering at
least one glucose-related sensor data point when glucose transport
is determined to be unstable.
Another aspect of the preferred embodiments is a system for
measuring glucose in a host, comprising a glucose-measuring
electrode configured to generate a first signal comprising at least
one glucose-related sensor data point, wherein the
glucose-measuring electrode is disposed beneath an enzymatic
portion of a membrane system on a glucose sensor and a
transport-measuring electrode configured to generate a second
signal comprising at least one non-glucose constant analyte data
point, wherein the transport-measuring electrode is situated
beneath the membrane system on the glucose sensor. One embodiment
further comprises a processor module configured to monitor the
second signal whereby a sensitivity change associated with
transport of the non-glucose constant analyte through the membrane
system over a time period is measured. In one embodiment, the
transport-measuring electrode is configured to measure oxygen. In
one embodiment, the processor module is configured to determine
whether a glucose-to-oxygen ratio exceeds a threshold level,
wherein a value is calculated from the first signal and the second
signal, wherein the value is indicative of the glucose-to-oxygen
ratio. In one embodiment, the processor module is configured to
calibrate the glucose-related sensor data point in response to the
sensitivity change. In one embodiment, the processor module is
configured to receive reference data from a reference analyte
monitor, the reference data comprising at least one reference data
point, wherein the processor module is configured to use the
reference data point for calibrating the glucose-related sensor
data point. In one embodiment, the processor module is configured
to use the sensitivity change for calibrating the glucose-related
sensor data point. In one embodiment, the processor module is
configured to calibrate the glucose-related sensor data point
repeatedly at a frequency, wherein the frequency is selected based
on the sensitivity change. One embodiment further comprises a
stability module configured to determine a stability of glucose
transport through the membrane system, wherein the stability of
glucose transport is correlated with the sensitivity change. In one
embodiment, the processor module is configured to prohibit
calibration of the glucose-related sensor data point when the
stability of glucose transport falls below a threshold. In one
embodiment, the processor module is configured to initiate
filtering of the glucose-related sensor data point when the
stability of glucose transport falls below a threshold.
Another aspect of the preferred embodiments is a method for
processing data from a glucose sensor in a host, comprising: 1)
measuring a first signal associated with glucose and non-glucose
related electroactive compounds, wherein the first signal is
measured at a first electrode disposed beneath an active enzymatic
portion of a membrane system; 2) measuring a second signal
associated with a non-glucose related electroactive compound,
wherein the second signal is measured at a second electrode that is
disposed beneath a non-enzymatic portion of the membrane system;
and 3) monitoring the second signal over a time period, whereby a
change in the non-glucose related electroactive compound in the
host is measured. One embodiment further comprises a step of
subtracting the second signal from the first signal, whereby a
differential signal comprising at least one glucose sensor data
point is determined. The step of subtracting may be performed
electronically in the sensor. Alternatively, the step of
subtracting may be performed digitally in the sensor or an
associated receiver. One embodiment further comprises calibrating
the glucose sensor, wherein the step of calibrating comprises: 1)
receiving reference data from a reference analyte monitor, the
reference data comprising at least two reference data points; 2)
providing at least two matched data pairs by matching the reference
data to substantially time corresponding sensor data; and 3)
calibrating the glucose sensor using the two or more matched data
pairs and the differential signal. One embodiment further comprises
a step of calibrating the glucose sensor in response to a change in
the non-glucose related electroactive compound over the time
period. The step of calibrating may comprise receiving reference
data from a reference analyte monitor, the reference data
comprising at least one reference data point. The step of
calibrating may comprise using the change in the non-glucose
related electroactive compound over the time period to calibrate
the glucose sensor. The step of calibrating may be performed
repeatedly at a frequency, wherein the frequency is selected based
on the change in the non-glucose related electroactive compound
over the time period. One embodiment further comprises prohibiting
calibration of the glucose sensor when the change in the
non-glucose related electroactive compound rises above a threshold
during the time period. One embodiment further comprises filtering
the glucose sensor data point when the change in the non-glucose
related electroactive compound rises above a threshold during the
time period. One embodiment further comprises measuring a third
signal in the host by obtaining at least one non-glucose constant
data point, wherein the third signal is measured beneath the
membrane system. One embodiment further comprises monitoring the
third signal over a time period, whereby a sensitivity change
associated with solute transport through the membrane system is
measured. In one embodiment, an oxygen-measuring electrode disposed
beneath the non-enzymatic portion of the membrane system measures
the third signal. In one embodiment, the first electrode measures
the third signal by incrementally measuring oxygen. In one
embodiment, an oxygen sensor disposed beneath the membrane system
measures the third signal. One embodiment further comprises
determining whether a glucose-to-oxygen ratio exceeds a threshold
level by calculating a value from the first signal and the second
signal, wherein the value is indicative of the glucose-to-oxygen
ratio. One embodiment further comprises calibrating the glucose
sensor in response to the sensitivity change measured over a time
period. The step of calibrating may comprise receiving reference
data from a reference analyte monitor, the reference data
comprising at least one reference data point. The step of
calibrating may comprise using the sensitivity change. The step of
calibrating may be performed repeatedly at a frequency, wherein the
frequency is selected based on the sensitivity change. One
embodiment further comprises determining a glucose transport
stability through the membrane system, wherein the glucose
transport stability corresponds to the sensitivity change over a
period of time. One embodiment further comprises prohibiting
calibration of the glucose sensor when the glucose transport
stability falls below a threshold. One embodiment further comprises
filtering the glucose-related sensor data point when the glucose
transport stability falls below a threshold.
Still another aspect of the preferred embodiments is a system for
measuring glucose in a host, comprising a first working electrode
configured to generate a first signal associated with a glucose
related electroactive compound and a non-glucose related
electroactive compound, wherein the first electrode is disposed
beneath an active enzymatic portion of a membrane system on a
glucose sensor; a second working electrode configured to generate a
second signal associated with the non-glucose related electroactive
compound, wherein the second electrode is disposed beneath a
non-enzymatic portion of the membrane system on the glucose sensor;
and a processor module configured to monitor the second signal over
a time period, whereby a change in the non-glucose related
electroactive compound is measured. One embodiment further
comprises a subtraction module configured to subtract the second
signal from the first signal, whereby a differential signal
comprising at least one glucose sensor data point is determined.
The subtraction module may comprise a differential amplifier
configured to electronically subtract the second signal from the
first signal. The subtraction module may comprise at least one of
hardware and software configured to digitally subtract the second
signal from the first signal. One embodiment further comprises a
reference electrode, wherein the first working electrode and the
second working electrode are operatively associated with the
reference electrode. One embodiment further comprises a counter
electrode, wherein the first working electrode and the second
working electrode are operatively associated with the counter
electrode. One embodiment further comprises a first reference
electrode and a second reference electrode, wherein the first
reference electrode is operatively associated with the first
working electrode, and wherein the second reference electrode is
operatively associated with the second working electrode. One
embodiment further comprises a first counter electrode and a second
counter electrode, wherein the first counter electrode is
operatively associated with the first working electrode, and
wherein the second counter electrode is operatively associated with
the second working electrode. One embodiment further comprises a
reference input module adapted to obtain reference data from a
reference analyte monitor, the reference data comprising at least
one reference data point, wherein the processor module is
configured to format at least one matched data pair by matching the
reference data to substantially time corresponding glucose sensor
data and subsequently calibrating the system using at least two
matched data pairs and the differential signal. In one embodiment,
the processor module is configured to calibrate the system in
response to the change in the non-glucose related electroactive
compound in the host over the time period. In one embodiment, the
processor module is configured to request reference data from a
reference analyte monitor, the reference data comprising at least
one reference data point, wherein the processor module is
configured to recalibrate the system using the reference data. In
one embodiment, the processor module is configured to recalibrate
the system using the change in the non-glucose related
electroactive compound measured over the time period. In one
embodiment, the processor module is configured to repeatedly
recalibrate at a frequency, wherein the frequency is selected based
on the change in the non-glucose related electroactive compound
over the time period. In one embodiment, the processor module is
configured to prohibit calibration of the system when a change in
the non-glucose related electroactive compound rises above a
threshold during the time period. In one embodiment, the processor
module is configured to filter the glucose sensor data point when
the change in the non-glucose related electroactive compound rises
above a threshold during the time period. One embodiment further
comprises a third electrode configured to generate a third signal,
the third signal comprising at least one non-glucose constant
analyte data point, wherein the third electrode is disposed beneath
the membrane system on the sensor. The third electrode may be
configured to measure oxygen. In one embodiment, the processor
module is configured to determine whether a glucose-to-oxygen ratio
exceeds a threshold level, wherein a value indicative of the
glucose-to-oxygen ratio is calculated from the first signal and the
second signal. In one embodiment, the processor module is
configured to monitor the third signal over a time period, whereby
a sensitivity change associated with solute transport through the
membrane system is measured. In one embodiment, the processor
module is configured to calibrate the glucose-related sensor data
point in response to the sensitivity change. In one embodiment, the
processor module is configured to receive reference data from a
reference analyte monitor, the reference data comprising at least
one reference data point, wherein the processor module is
configured to calibrate the glucose sensor data point using the
reference data point. In one embodiment, the processor module is
configured to calibrate the glucose-related sensor data point
repeatedly at a frequency, wherein the frequency is selected based
on the sensitivity change. One embodiment further comprises a
stability module configured to determine a stability of glucose
transport through the membrane system, wherein the stability of
glucose transport is correlated with the sensitivity change. In one
embodiment, the processor module is configured to prohibit
calibration of the glucose-related sensor data point when the
stability of glucose transport falls below a threshold. In one
embodiment, the processor module is configured to filter the
glucose-related sensor data point when the stability of glucose
transport falls below a threshold.
In a first aspect, an analyte sensor configured for insertion into
a host for measuring an analyte in the host is provided the sensor
comprising a first working electrode disposed beneath an active
enzymatic portion of a sensor membrane; and a second working
electrode disposed beneath an inactive-enzymatic or a non-enzymatic
portion of a sensor membrane, wherein the first working electrode
and the second working electrode each integrally form at least a
portion of the sensor.
In an embodiment of the first aspect, the first working electrode
and the second working electrode are coaxial.
In an embodiment of the first aspect, at least one of the first
working electrode and the second working electrode is twisted or
helically wound to integrally form at least a portion of the
sensor.
In an embodiment of the first aspect, the first working electrode
and the second working electrode are twisted together to integrally
form an in vivo portion of the sensor.
In an embodiment of the first aspect, one of the first working
electrode and the second working electrode is deposited or plated
over the other of the first working electrode and the second
working electrode.
In an embodiment of the first aspect, the first working electrode
and the second working electrode each comprise a first end and a
second end, wherein the first ends are configured for insertion in
the host, and wherein the second ends are configured for electrical
connection to sensor electronics.
In an embodiment of the first aspect, the second ends are
coaxial.
In an embodiment of the first aspect, the second ends are
stepped.
In an embodiment of the first aspect, wherein the sensor further
comprises at least one additional electrode selected from the group
consisting of a reference electrode and a counter electrode.
In an embodiment of the first aspect, the additional electrode,
together with the first working electrode and the second working
electrode, integrally form at least a portion of the sensor.
In an embodiment of the first aspect, the additional electrode is
located at a position remote from the first and second working
electrodes.
In an embodiment of the first aspect, a surface area of the
additional electrode is at least six times a surface area of at
least one of the first working electrode and the second working
electrode.
In an embodiment of the first aspect, the sensor is configured for
implantation into the host.
In an embodiment of the first aspect, the sensor is configured for
subcutaneous implantation in a tissue of a host.
In an embodiment of the first aspect, the sensor is configured for
indwelling in a blood stream of a host.
In an embodiment of the first aspect, the sensor substantially
continuously measures an analyte concentration in a host.
In an embodiment of the first aspect, the sensor comprises a
glucose sensor, and wherein the first working electrode is
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential.
In an embodiment of the first aspect, the second working electrode
is configured to generate a second signal associated with noise of
the glucose sensor, the noise comprising signal contribution due to
non-glucose related electroactive compounds with an oxidation
potential that substantially overlaps with the first oxidation
potential.
In an embodiment of the first aspect, the non-glucose related
electroactive species comprises at least one species selected from
the group consisting of interfering species, non-reaction-related
hydrogen peroxide, and other electroactive species.
In an embodiment of the first aspect, the sensor further comprises
electronics operably connected to the first working electrode and
the second working electrode, and configured to provide the first
signal and the second signal to generate glucose concentration data
substantially without signal contribution due to
non-glucose-related noise.
In an embodiment of the first aspect, the sensor further comprises
a non-conductive material positioned between the first working
electrode and the second working electrode.
In an embodiment of the first aspect, each of the first working
electrode, the second working electrode, and the non-conductive
material are configured to provide at least two functions selected
from the group consisting of electrical conductance, insulative
property, structural support, and diffusion barrier.
In an embodiment of the first aspect, the sensor comprises a
diffusion barrier configured to substantially block diffusion of at
least one of an analyte and a co-analyte between the first working
electrode and the second working electrode.
In a second aspect, a glucose sensor configured for insertion into
a host for measuring a glucose concentration in the host is
provided, the sensor comprising a first working electrode
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential; and a second working electrode configured to
generate a second signal associated with noise of the glucose
sensor comprising signal contribution due to non-glucose related
electroactive compounds with an oxidation potential that
substantially overlaps with the first oxidation potential, wherein
the first working electrode and the second working electrode each
integrally form at least a portion of the sensor.
In an embodiment of the second aspect, the first working electrode
and the second working electrode integrally form a substantial
portion of the sensor configured for insertion in the host.
In an embodiment of the second aspect, the sensor further comprises
a reference electrode, wherein the first working electrode, the
second working electrode, and the reference electrode each
integrally form a substantial portion of the sensor configured for
insertion in the host.
In an embodiment of the second aspect, the sensor further comprises
an insulator, wherein the first working electrode, the second
working electrode, and the insulator each integrally form a
substantial portion of the sensor configured for insertion in the
host.
In a third aspect, a system configured for measuring a glucose
concentration in a host is provided, the system comprising a
processor module configured to receive or process a first signal
associated with glucose and non-glucose related electroactive
compounds, the glucose and non-glucose related electroactive
compounds having a first oxidation potential, and to receive or
process a second signal associated with noise of the glucose sensor
comprising signal contribution due to non-glucose related
electroactive compounds with an oxidation potential that
substantially overlaps with the first oxidation potential, wherein
the first working electrode and the second working electrode each
integrally form at least a portion of the sensor, and wherein the
processor module is further configured to process the first signal
and the second signal to generate glucose concentration data
substantially without signal contribution due to
non-glucose-related noise.
In an embodiment of the third aspect, the first working electrode
and the second working electrode are coaxial.
In an embodiment of the third aspect, at least one of the first
working electrode and the second working electrode is twisted or
helically wound to form at least a portion of the sensor.
In an embodiment of the third aspect, the first working electrode
and the second working electrode are twisted together to form an in
vivo portion of the sensor.
In an embodiment of the third aspect, one of the first working
electrode and the second working electrode is deposited or plated
over the other of the first working electrode and the second
working electrode.
In an embodiment of the third aspect, the first working electrode
and the second working electrode each comprise a first end and a
second end, wherein the first ends are configured for insertion in
the host, and wherein the second ends are configured for electrical
connection to sensor electronics.
In an embodiment of the third aspect, the second ends are
coaxial.
In an embodiment of the third aspect, the second ends are
stepped.
In a fourth aspect, an analyte sensor configured for insertion into
a host for measuring an analyte in the host is provided, the sensor
comprising a first working electrode disposed beneath an active
enzymatic portion of a membrane; a second working electrode
disposed beneath an inactive-enzymatic or non-enzymatic portion of
a membrane; and a non-conductive material located between the first
working electrode and the second working electrode, wherein each of
the first working electrode, the second working electrode, and the
non-conductive material are configured provide at least two
functions selected from the group consisting of electrical
conductance, insulative property, structural support, and diffusion
barrier.
In an embodiment of the fourth aspect, each of the first working
electrode and the second working electrode are configured to
provide electrical conductance and structural support.
In an embodiment of the fourth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide electrical conductance and structural
support.
In an embodiment of the fourth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide electrical conductance and a diffusion
barrier.
In an embodiment of the fourth aspect, the non-conductive material
is configured to provide an insulative property and structural
support.
In an embodiment of the fourth aspect, the non-conductive material
is configured to provide an insulative property and a diffusion
barrier.
In an embodiment of the fourth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide a diffusion barrier and structural
support.
In an embodiment of the fourth aspect, the non-conductive material
is configured to provide a diffusion barrier and structural
support.
In an embodiment of the fourth aspect, the sensor further comprises
at least one of a reference electrode and a counter electrode.
In an embodiment of the fourth aspect, at least one of the
reference electrode and the counter electrode, together with the
first working electrode and the second working electrode,
integrally form at least a portion of the sensor.
In an embodiment of the fourth aspect, at least one of the
reference electrode and the counter electrode is located at a
position remote from the first working electrode and the second
working electrode.
In an embodiment of the fourth aspect, a surface area of at least
one of the reference electrode and the counter electrode is at
least six times a surface area of at least one of the first working
electrode and the second working electrode.
In an embodiment of the fourth aspect, the sensor is configured for
implantation into the host.
In an embodiment of the fourth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
In an embodiment of the fourth aspect, the sensor is configured for
indwelling in a blood stream of the host.
In an embodiment of the fourth aspect, the sensor substantially
continuously measures an analyte concentration in the host.
In an embodiment of the fourth aspect, the sensor comprises a
glucose sensor, and wherein the first working electrode is
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related compounds having a first oxidation
potential.
In an embodiment of the fourth aspect, the second working electrode
is configured to generate a second signal associated with noise of
the glucose sensor comprising signal contribution due to
non-glucose related electroactive compounds with an oxidation
potential that substantially overlaps with the first oxidation
potential.
In an embodiment of the fourth aspect, the non-glucose related
electroactive species comprises at least one species selected from
the group consisting of interfering species, non-reaction-related
hydrogen peroxide, and other electroactive species.
In an embodiment of the fourth aspect, the sensor further comprises
electronics operably connected to the first working electrode and
the second working electrode, and configured to provide the first
signal and the second signal to generate glucose concentration data
substantially without signal contribution due to
non-glucose-related noise.
In an embodiment of the fourth aspect, the sensor further comprises
a non-conductive material positioned between the first working
electrode and the second working electrode.
In an embodiment of the fourth aspect, the first working electrode,
the second working electrode, and the non-conductive material
integrally form at least a portion of the sensor.
In an embodiment of the fourth aspect, the first working electrode
and the second working electrode each integrally form a substantial
portion of the sensor configured for insertion in the host.
In an embodiment of the fourth aspect, the sensor further comprises
a reference electrode, wherein the first working electrode, the
second working electrode, and the reference electrode each
integrally form a substantial portion of the sensor configured for
insertion in the host.
In an embodiment of the fourth aspect, the sensor further comprises
an insulator, wherein the first working electrode, the second
working electrode, and the insulator each integrally form a
substantial portion of the sensor configured for insertion in the
host.
In an embodiment of the fourth aspect, the sensor comprises a
diffusion barrier configured to substantially block diffusion of an
analyte or a co-analyte between the first working electrode and the
second working electrode.
In a fifth aspect, a glucose sensor configured for insertion into a
host for measuring a glucose concentration in the host is provided,
the sensor comprising a first working electrode configured to
generate a first signal associated with glucose and non-glucose
related electroactive compounds, the glucose and non-glucose
related electroactive compounds having a first oxidation potential;
a second working electrode configured to generate a second signal
associated with noise of the glucose sensor comprising signal
contribution due to non-glucose related electroactive compounds
with an oxidation potential that substantially overlaps with the
first oxidation potential; and a non-conductive material located
between the first working electrode and the second working
electrode, wherein each of the first working electrode, the second
working electrode, and the non-conductive material are configured
provide at least two functions selected from the group consisting
of electrical conductance, insulative property, structural support,
and diffusion barrier.
In an embodiment of the fifth aspect, each of the first working
electrode and the second working electrode are configured to
provide electrical conductance and structural support.
In an embodiment of the fifth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide electrical conductance and structural
support.
In an embodiment of the fifth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide electrical conductance and a diffusion
barrier.
In an embodiment of the fifth aspect, the sensor further comprises
a reference electrode, wherein the reference electrode is
configured to provide a diffusion barrier and structural
support.
In an embodiment of the fifth aspect, the non-conductive material
is configured to provide an insulative property and structural
support.
In an embodiment of the fifth aspect, the non-conductive material
is configured to provide an insulative property and a diffusion
barrier.
In an embodiment of the fifth aspect, the non-conductive material
is configured to provide a diffusion barrier and structural
support.
In a sixth aspect, an analyte sensor configured for insertion into
a host for measuring an analyte in the host is provided, the sensor
comprising a first working electrode disposed beneath an active
enzymatic portion of a membrane; a second working electrode
disposed beneath an inactive-enzymatic or non-enzymatic portion of
a membrane; and an insulator located between the first working
electrode and the second working electrode, wherein the sensor
comprises a diffusion barrier configured to substantially block
diffusion of at least one of an analyte and a co-analyte between
the first working electrode and the second working electrode.
In an embodiment of the sixth aspect, the diffusion barrier
comprises a physical diffusion barrier configured to physically
block or spatially block a substantial amount of diffusion of at
least one of the analyte and the co-analyte between the first
working electrode and the second working electrode.
In an embodiment of the sixth aspect, the physical diffusion
barrier comprises the insulator.
In an embodiment of the sixth aspect, the physical diffusion
barrier comprises the reference electrode.
In an embodiment of the sixth aspect, a dimension of the first
working electrode and a dimension of the second working electrode
relative to an in vivo portion of the sensor provide the physical
diffusion barrier.
In an embodiment of the sixth aspect, the physical diffusion
barrier comprises a membrane.
In an embodiment of the sixth aspect, the membrane is configured to
block diffusion of a substantial amount of at least one of the
analyte and the co-analyte between the first working electrode and
the second working electrode.
In an embodiment of the sixth aspect, the diffusion barrier
comprises a temporal diffusion barrier configured to block or avoid
a substantial amount of diffusion or reaction of at least one of
the analyte and the co-analyte between the first and second working
electrodes.
In an embodiment of the sixth aspect, the sensor further comprises
a potentiostat configured to bias the first working electrode and
the second working electrode at substantially overlapping oxidation
potentials, and wherein the temporal diffusion barrier comprises
pulsed potentials of the first working electrode and the second
working electrode to block or avoid a substantial amount of
diffusion or reaction of at least one of the analyte and the
co-analyte between the first working electrode and the second
working electrode.
In an embodiment of the sixth aspect, the sensor further comprises
a potentiostat configured to bias the first working electrode and
the second working electrode at substantially overlapping oxidation
potentials, and wherein the temporal diffusion barrier comprises
oscillating bias potentials of the first working electrode and the
second working electrode to block or avoid a substantial amount of
diffusion or reaction of at least one of the analyte and the
co-analyte between the first working electrode and the second
working electrode.
In an embodiment of the sixth aspect, the analyte sensor is
configured to indwell in a blood stream of the host, and wherein
the diffusion barrier comprises a configuration of the first
working electrode and the second working electrode that provides a
flow path diffusion barrier configured to block or avoid a
substantial amount of diffusion of at least one of the analyte and
the co-analyte between the first working electrode and the second
working electrode.
In an embodiment of the sixth aspect, the flow path diffusion
barrier comprises a location of the first working electrode
configured to be upstream from the second working electrode when
inserted into the blood stream.
In an embodiment of the sixth aspect, the flow path diffusion
barrier comprises a location of the first working electrode
configured to be downstream from the second working electrode when
inserted into the blood stream.
In an embodiment of the sixth aspect, the flow path diffusion
barrier comprises an offset of the first working electrode relative
to the second working electrode when inserted into the blood
stream.
In an embodiment of the sixth aspect, the flow path diffusion
barrier is configured to utilize a shear of a blood flow of the
host between the first working electrode and the second working
electrode when inserted into the blood stream.
In an embodiment of the sixth aspect, the sensor is a glucose
sensor, and wherein the diffusion barrier is configured to
substantially block diffusion of at least one of glucose and
hydrogen peroxide between the first working electrode and the
second working electrode.
In an embodiment of the sixth aspect, the sensor further comprises
at least one of a reference electrode and a counter electrode.
In an embodiment of the sixth aspect, the reference electrode or
the counter electrode, together with the first working electrode,
the second working electrode and the insulator, integrally form at
least a portion of the sensor.
In an embodiment of the sixth aspect, the reference electrode or
the counter electrode is located at a position remote from the
first working electrode and the second working electrode.
In an embodiment of the sixth aspect, a surface area of at least
one of the reference electrode and the counter electrode is at
least six times a surface area of at least one of the first working
electrode and the second working electrode.
In an embodiment of the sixth aspect, the sensor is configured for
implantation into the host.
In an embodiment of the sixth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
In an embodiment of the sixth aspect, the sensor is configured for
indwelling in a blood stream of the host.
In an embodiment of the sixth aspect, sensor substantially
continuously measures an analyte concentration in the host.
In an embodiment of the sixth aspect, the analyte sensor comprises
a glucose sensor and wherein the first working electrode is
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential.
In an embodiment of the sixth aspect, the second working electrode
is configured to generate a second signal associated with noise of
the glucose sensor comprising signal contribution due to
non-glucose related electroactive compounds with an oxidation
potential that substantially overlaps with the first oxidation
potential.
In an embodiment of the sixth aspect, the non-glucose related
electroactive species comprise at least one species selected from
the group consisting of interfering species, non-reaction-related
hydrogen peroxide, and other electroactive species.
In an embodiment of the sixth aspect, the sensor further comprises
electronics operably connected to the first working electrode and
the second working electrode, and configured to provide the first
signal and the second signal to generate glucose concentration data
substantially without signal contribution due to
non-glucose-related noise.
In an embodiment of the sixth aspect, the first working electrode,
the second working electrode, and the insulator integrally form a
substantial portion of the sensor configured for insertion in the
host.
In an embodiment of the sixth aspect, the sensor further comprises
a reference electrode, wherein the first working electrode, the
second working electrode, and the reference electrode integrally
form a substantial portion of the sensor configured for insertion
in the host.
In an embodiment of the sixth aspect, each of the first working
electrode, the second working electrode, and the non-conductive
material are configured provide at least two functions selected
from the group consisting of electrical conductance, insulative
property, structural support, and diffusion barrier.
In a seventh aspect, a glucose sensor configured for insertion into
a host for measuring a glucose concentration in the host is
provided, the sensor comprising a first working electrode
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential; a second working electrode configured to
generate a second signal associated with noise of the glucose
sensor comprising signal contribution due to non-glucose related
electroactive compounds with an oxidation potential that
substantially overlaps with the first oxidation potential; and a
non-conductive material located between the first working electrode
and the second working electrode, wherein the sensor comprises a
diffusion barrier configured to substantially block diffusion of at
least one of the analyte and the co-analyte between the first
working electrode and the second working electrode.
In an embodiment of the seventh aspect, the diffusion barrier
comprises a physical diffusion barrier configured to physically or
spatially block a substantial amount of diffusion of at least one
of the analyte and the co-analyte between the first working
electrode and the second working electrode.
In an embodiment of the seventh aspect, the diffusion barrier
comprises a temporal diffusion barrier configured to block or avoid
a substantial amount of diffusion or reaction of at least one of
the analyte and the co-analyte between the first working electrode
and the second working electrode.
In an embodiment of the seventh aspect, the analyte sensor is
configured to indwell in a blood stream of the host, and wherein
the diffusion barrier comprises a configuration of the first
working electrode and the second working electrode that provides a
flow path diffusion barrier configured to block or avoid a
substantial amount of diffusion of at least one of the analyte and
the co-analyte between the first working electrode and the second
working electrode.
In an embodiment of the seventh aspect, the sensor further
comprises at least one of a reference electrode and a counter
electrode.
In an embodiment of the seventh aspect, the sensor is configured
for implantation into the host.
In an embodiment of the seventh aspect, the sensor substantially
continuously measures an analyte concentration in the host.
In an embodiment of the seventh aspect, the sensor further
comprises electronics operably connected to the first working
electrode and the second working electrode, and configured to
provide the first signal and the second signal to generate glucose
concentration data substantially without signal contribution due to
non-glucose-related noise.
In an embodiment of the seventh aspect, the first working
electrode, the second working electrode, and the insulator
integrally form a substantial portion of the sensor configured for
insertion in the host.
In an embodiment of the seventh aspect, each of the first working
electrode, the second working electrode, and the non-conductive
material are configured provide at least two functions selected
from the group consisting of: electrical conductance, insulative
property, structural support, and diffusion barrier.
In an eighth aspect, a glucose sensor system configured for
insertion into a host for measuring a glucose concentration in the
host is provided, the sensor comprising a first working electrode
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and
non-glucose related electroactive compounds having a first
oxidation potential; a second working electrode configured to
generate a second signal associated with noise of the glucose
sensor comprising signal contribution due to non-glucose related
electroactive compounds with an oxidation potential that
substantially overlaps with the first oxidation potential; and
electronics operably connected to the first working electrode and
the second working electrode and configured to process the first
signal and the second signal to generate a glucose concentration
substantially without signal contribution due to non-glucose
related noise.
In an embodiment of the eighth aspect, the non-glucose related
noise is substantially non-constant.
In an embodiment of the eighth aspect, the electronics are
configured to substantially remove noise caused by mechanical
factors.
In an embodiment of the eighth aspect, the mechanical factors are
selected from the group consisting of macro-motion of the sensor,
micro-motion of the sensor, pressure on the sensor, and stress on
the sensor.
In an embodiment of the eighth aspect, the first working electrode
and the second working electrode are configured to substantially
equally measure noise due to mechanical factors, whereby noise
caused by mechanical factors is substantially removed.
In an embodiment of the eighth aspect, the electronics are
configured to substantially remove noise caused by at least one of
biochemical factors and chemical factors.
In an embodiment of the eighth aspect, the at least one of the
biochemical factors and the chemical factors are substantially
non-constant and are selected from the group consisting of
compounds with electroactive acidic groups, compounds with
electroactive amine groups, compounds with electroactive sulfhydryl
groups, urea, lactic acid, phosphates, citrates, peroxides, amino
acids, amino acid precursors, amino acid break-down products,
nitric oxide, nitric oxide-donors, nitric oxide-precursors,
electroactive species produced during cell metabolism,
electroactive species produced during wound healing, and
electroactive species that arise during body pH changes.
In an embodiment of the eighth aspect, the first working electrode
and the second working electrode are configured to substantially
equally measure noise due to at least one of the biochemical
factors and the chemical factors whereby noise caused by at least
one of the biochemical factors and the chemical factors can be
substantially removed.
In an embodiment of the eighth aspect, the electronics are
configured to subtract the second signal from the first signal,
whereby a differential signal comprising at least one glucose
sensor data point is determined.
In an embodiment of the eighth aspect, the electronics comprise a
differential amplifier configured to electronically subtract the
second signal from the first signal.
In an embodiment of the eighth aspect, the electronics comprise at
least one of hardware and software configured to digitally subtract
the second signal from the first signal.
In an embodiment of the eighth aspect, the first working electrode
and the second working electrode are configured to be impacted by
mechanical factors and biochemical factors to substantially the
same extent.
In an embodiment of the eighth aspect, the first working electrode
and the second working electrode have a configuration selected from
the group consisting of coaxial, helically twisted, bundled,
symmetrical, and combinations thereof.
In an embodiment of the eighth aspect, the sensor further comprises
a non-conductive material positioned between the first working
electrode and the second working electrode.
In an embodiment of the eighth aspect, each of the first working
electrode, the second working electrode, and the non-conductive
material are configured provide at least two functions selected
from the group consisting of electrical conductance, insulative
property, structural support, and diffusion barrier.
In an embodiment of the eighth aspect, the sensor comprises a
diffusion barrier configured to substantially block diffusion of at
least one of the analyte and the co-analyte between the first
working electrode and the second working electrode.
In an embodiment of the eighth aspect, the first working electrode,
the second working electrode, and the insulator integrally form a
substantial portion of the sensor configured for insertion in the
host.
In an embodiment of the eighth aspect, the sensor further comprises
a reference electrode, wherein the first working electrode, the
second working electrode, and the reference electrode integrally
form a substantial portion of the sensor configured for insertion
in the host.
In a ninth aspect, an analyte sensor configured for insertion into
a host for measuring an analyte in the host is provided, the sensor
comprising a first working electrode disposed beneath an active
enzymatic portion of a membrane; a second working electrode
disposed beneath an inactive-enzymatic or non-enzymatic portion of
a membrane, wherein the first working electrode and the second
working electrode are configured to substantially equally measure
non-analyte related noise, whereby the noise is substantially
removed; and electronics operably connected to the first working
electrode and the second working electrode, and configured to
process the first signal and the second signal to generate sensor
analyte data substantially without signal contribution due to
non-analyte related noise.
In an embodiment of the ninth aspect, the non-glucose related noise
is substantially non-constant.
In an embodiment of the ninth aspect, the non-analyte related noise
is due to a factor selected from the group consisting of mechanical
factors, biochemical factors, chemical factors, and combinations
thereof.
In an embodiment of the ninth aspect, the electronics are
configured to substantially remove noise caused by mechanical
factors.
In an embodiment of the ninth aspect, the mechanical factors are
selected from the group consisting of macro-motion of the sensor,
micro-motion of the sensor, pressure on the sensor, and stress on
the sensor.
In an embodiment of the ninth aspect, the first working electrode
and the second working electrode are configured to substantially
equally measure noise due to mechanical factors, whereby noise
caused by mechanical factors can be substantially removed.
In an embodiment of the ninth aspect, the electronics are
configured to substantially remove noise caused by at least one of
biochemical factors and chemical factors.
In an embodiment of the ninth aspect, at least one of the
biochemical factors and the chemical factors are substantially
non-constant and are selected from the group consisting of
compounds with electroactive acidic groups, compounds with
electroactive amine groups, compounds with electroactive sulfhydryl
groups, urea, lactic acid, phosphates, citrates, peroxides, amino
acids, amino acid precursors, amino acid break-down products,
nitric oxide, nitric oxide-donors, nitric oxide-precursors,
electroactive species produced during cell metabolism,
electroactive species produced during wound healing, and
electroactive species that arise during body pH changes.
In an embodiment of the ninth aspect, the first working electrode
and the second working electrode are configured to substantially
equally measure noise due to at least one of biochemical factors
and chemical factors, whereby noise caused by at least one of the
biochemical factors and the chemical factors is substantially
removed.
In an embodiment of the ninth aspect, the sensor further comprises
at least one of a reference electrode and a counter electrode.
In an embodiment of the ninth aspect, at least one of the reference
electrode and the counter electrode, together with the first
working electrode and the second working electrode, integrally form
at least a portion of the sensor.
In an embodiment of the ninth aspect, at least one of the reference
electrode and the counter electrode is located at a position remote
from the first working electrode and the second working
electrode.
In an embodiment of the ninth aspect, a surface area of at least
one of the reference electrode and the counter electrode is at
least six times a surface area of at least one of the first working
electrode and the second working electrode.
In an embodiment of the ninth aspect, the sensor is configured for
implantation into the host.
In an embodiment of the ninth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
In an embodiment of the ninth aspect, the sensor is configured for
indwelling in a blood stream of the host.
In an embodiment of the ninth aspect, the sensor substantially
continuously measures an analyte concentration of the host.
In an embodiment of the ninth aspect, the analyte sensor comprises
a glucose sensor, and wherein the first working electrode is
configured to generate a first signal associated with glucose and
non-glucose related electroactive compounds, the glucose and the
non-glucose related electroactive compounds having a first
oxidation potential.
In an embodiment of the ninth aspect, the second working electrode
is configured to generate a second signal associated with noise of
the glucose sensor comprising signal contribution due to
non-glucose related electroactive compounds with an oxidation
potential that substantially overlaps with the first oxidation
potential.
In an embodiment of the ninth aspect, the non-glucose related
electroactive species comprises at least one species selected from
the group consisting of interfering species, non-reaction-related
hydrogen peroxide, and other electroactive species.
In an embodiment of the ninth aspect, the sensor further comprises
a non-conductive material positioned between the first working
electrode and the second working electrode.
In an embodiment of the ninth aspect, each of the first working
electrode, the second working electrode, and the non-conductive
material are configured provide at least two functions selected
from the group consisting of: electrical conductance, insulative
property, structural support, and diffusion barrier.
In an embodiment of the ninth aspect, the sensor comprises a
diffusion barrier configured to substantially block diffusion of at
least one of an analyte and a co-analyte between the first working
electrode and the second working electrode.
In an embodiment of the ninth aspect, the first working electrode,
the second working electrode, and the insulator integrally form a
substantial portion of the sensor configured for insertion in the
host.
In an embodiment of the ninth aspect, the sensor further comprises
a reference electrode, wherein the first working electrode, the
second working electrode, and the reference electrode integrally
form a substantial portion of the sensor configured for insertion
in the host.
In an embodiment of the ninth aspect, the first working electrode
and the second working electrode are configured to be impacted by
mechanical factors and biochemical factors to substantially the
same extent.
In an embodiment of the ninth aspect, the first working electrode
and the second working electrode have a configuration selected from
the group consisting of coaxial, helically twisted, bundled,
symmetrical, and combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a perspective view of a continuous analyte sensor,
including an implantable body with a membrane system disposed
thereon.
FIG. 1B is an expanded view of an alternative embodiment of a
continuous analyte sensor, illustrating the in vivo portion of the
sensor.
FIG. 2A is a schematic view of a membrane system in one embodiment,
configured for deposition over the electroactive surfaces of the
analyte sensor of FIG. 1A.
FIG. 2B is a schematic view of a membrane system in an alternative
embodiment, configured for deposition over the electroactive
surfaces of the analyte sensor of FIG. 1B.
FIG. 3A which is a cross-sectional exploded schematic view of a
sensing region of a continuous glucose sensor in one embodiment
wherein an active enzyme of an enzyme domain is positioned only
over the glucose-measuring working electrode.
FIG. 3B is a cross-sectional exploded schematic view of a sensing
region of a continuous glucose sensor in another embodiment,
wherein an active portion of the enzyme within the enzyme domain
positioned over the auxiliary working electrode has been
deactivated.
FIG. 4 is a block diagram that illustrates continuous glucose
sensor electronics in one embodiment.
FIG. 5 is a drawing of a receiver for the continuous glucose sensor
in one embodiment.
FIG. 6 is a block diagram of the receiver electronics in one
embodiment.
FIG. 7A1 is a schematic of one embodiment of a coaxial sensor
having axis A-A.
FIG. 7A2 is a cross-section of the sensor shown in FIG. 7A1.
FIG. 7B is a schematic of another embodiment of a coaxial
sensor.
FIG. 7C is a schematic of one embodiment of a sensor having three
electrodes.
FIG. 7D is a schematic of one embodiment of a sensor having seven
electrodes.
FIG. 7E is a schematic of one embodiment of a sensor having two
pairs of electrodes and insulating material.
FIG. 7F is a schematic of one embodiment of a sensor having two
electrodes separated by a reference electrode or insulating
material.
FIG. 7G is a schematic of another embodiment of a sensor having two
electrodes separated by a reference electrode or insulating
material.
FIG. 7H is a schematic of another embodiment of a sensor having two
electrodes separated by a reference electrode or insulating
material.
FIG. 7I is a schematic of another embodiment of a sensor having two
electrodes separated by reference electrodes or insulating
material.
FIG. 7J is a schematic of one embodiment of a sensor having two
electrodes separated by a substantially X-shaped reference
electrode or insulating material.
FIG. 7K is a schematic of one embodiment of a sensor having two
electrodes coated with insulating material, wherein one electrode
has a space for enzyme, the electrodes are separated by a distance
D and covered by a membrane system.
FIG. 7L is a schematic of one embodiment of a sensor having two
electrodes embedded in an insulating material.
FIG. 7M is a schematic of one embodiment of a sensor having
multiple working electrodes and multiple reference electrodes.
FIG. 7N is a schematic of one step of the manufacture of one
embodiment of a sensor having, embedded in insulating material, two
working electrodes separated by a reference electrode, wherein the
sensor is trimmed to a final size and/or shape.
FIG. 8A is a schematic on one embodiment of a sensor having two
working electrodes coated with insulating material, and separated
by a reference electrode.
FIG. 8B is a schematic of the second end (e.g., ex vivo terminus)
of the sensor of FIG. 8A having a stepped connection to the sensor
electronics.
FIG. 9A is a schematic of one embodiment of a sensor having two
working electrodes and a substantially cylindrical reference
electrode there around, wherein the second end (the end connected
to the sensor electronics) of the sensor is stepped.
FIG. 9B is a schematic of one embodiment of a sensor having two
working electrodes and an electrode coiled there around, wherein
the second end (the end connected to the sensor electronics) of the
sensor is stepped.
FIG. 10 is a schematic illustrating metabolism of glucose by
Glucose Oxidase (GOx) and one embodiment of a diffusion barrier D
that substantially prevents the diffusion of H.sub.2O.sub.2
produced on a first side of the sensor (e.g., from a first
electrode that has active GOx) to a second side of the sensor
(e.g., to the second electrode that lacks active GOx).
FIG. 11 is a schematic illustrating one embodiment of a triple
helical coaxial sensor having a stepped second terminus for
engaging the sensor electronics.
FIG. 12 is a graph that illustrates in vitro signal (raw counts)
detected from a sensor having three bundled wire electrodes with
staggered working electrodes. Plus GOx (thick line)=the electrode
with active GOx. No GOx (thin line)=the electrode with inactive or
no GOx.
FIG. 13 is a graph that illustrates in vitro signal (counts)
detected from a sensor having the configuration of the embodiment
shown in FIG. 7J (silver/silver chloride X-wire reference electrode
separating two platinum wire working electrodes). Plus GOx (thick
line)=the electrode with active GOx. No GOx (thin line)=the
electrode with inactive or no GOx.
FIG. 14 is a graph that illustrates an in vitro signal (counts)
detected from a dual-electrode sensor with a bundled configuration
similar to that shown in FIG. 7C (two platinum working electrodes
and one silver/silver chloride reference electrode, not
twisted).
FIG. 15 is a graph that illustrates an in vivo signal (counts)
detected from a dual-electrode sensor with a bundled configuration
similar to that shown in FIG. 7C (two platinum working electrodes,
not twisted, and one remotely disposed silver/silver chloride
reference electrode).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The following description and examples illustrate some exemplary
embodiments of the disclosed invention in detail. Those of skill in
the art will recognize that there are numerous variations and
modifications of this invention that are encompassed by its scope.
Accordingly, the description of a certain exemplary embodiment
should not be deemed to limit the scope of the present
invention.
Definitions
In order to facilitate an understanding of the disclosed invention,
a number of terms are defined below.
The term "analyte" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a substance
or chemical constituent in a biological fluid (for example, blood,
interstitial fluid, cerebral spinal fluid, lymph fluid or urine)
that can be analyzed. Analytes may include naturally occurring
substances, artificial substances, metabolites, and/or reaction
products. In some embodiments, the analyte for measurement by the
sensor heads, devices, and methods disclosed herein is glucose.
However, other analytes are contemplated as well, including but not
limited to acarboxyprothrombin; acylcarnitine; adenine
phosphoribosyl transferase; adenosine deaminase; albumin;
alpha-fetoprotein; amino acid profiles (arginine (Krebs cycle),
histidine/urocanic acid, homocysteine, phenylalanine/tyrosine,
tryptophan); andrenostenedione; antipyrine; arabinitol enantiomers;
arginase; benzoylecgonine (cocaine); biotinidase; biopterin;
c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin;
chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;
conjugated 1-.beta.hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
analyte-6-phosphate dehydrogenase, hemoglobinopathies, A,S,C,E,
D-Punjab, beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1,
Leber hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium
vivax, sexual differentiation, 21-deoxycortisol);
desbutylhalofantrine; dihydropteridine reductase;
diphtheria/tetanus antitoxin; erythrocyte arginase; erythrocyte
protoporphyrin; esterase D; fatty acids/acylglycines; free
.beta.-human chorionic gonadotropin; free erythrocyte porphyrin;
free thyroxine (FT4); free tri-iodothyronine (FT3);
fumarylacetoacetase; galactose/gal-1-phosphate;
galactose-1-phosphate uridyltransferase; gentamicin;
analyte-6-phosphate dehydrogenase; glutathione; glutathione
perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17 alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1,.beta.); lysozyme;
mefloquine; netilmicin; phenobarbitone; phenytoin;
phytanic/pristanic acid; progesterone; prolactin; prolidase; purine
nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);
selenium; serum pancreatic lipase; sissomicin; somatomedin C;
specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta
antibody, arbovirus, Aujeszky's disease virus, dengue virus,
Dracunculus medinensis, Echinococcus granulosus, Entamoeba
histolytica, enterovirus, Giardia duodenalis, Helicobacter pylori,
hepatitis B virus, herpes virus, HIV-1, IgE (atopic disease),
influenza virus, Leishmania donovani, leptospira,
measles/mumps/rubella, Mycobacterium leprae, Mycoplasma pneumoniae,
Myoglobin, Onchocerca volvulus, parainfluenza virus, Plasmodium
falciparum, poliovirus, Pseudomonas aeruginosa, respiratory
syncytial virus, rickettsia (scrub typhus), Schistosoma mansoni,
Toxoplasma gondii, Treponema pallidium, Trypanosoma cruzi/rangeli,
vesicular stomatitis virus, Wuchereria bancrofti, yellow fever
virus); specific antigens (hepatitis B virus, HIV-1);
succinylacetone; sulfadoxine; theophylline; thyrotropin (TSH);
thyroxine (T4); thyroxine-binding globulin; trace elements;
transferrin; UDP-galactose-4-epimerase; urea; uroporphyrinogen I
synthase; vitamin A; white blood cells; and zinc protoporphyrin.
Salts, sugar, protein, fat, vitamins, and hormones naturally
occurring in blood or interstitial fluids may also constitute
analytes in certain embodiments. The analyte may be naturally
present in the biological fluid, for example, a metabolic product,
a hormone, an antigen, an antibody, and the like. Alternatively,
the analyte may be introduced into the body, for example, a
contrast agent for imaging, a radioisotope, a chemical agent, a
fluorocarbon-based synthetic blood, or a drug or pharmaceutical
composition, including but not limited to insulin; ethanol;
cannabis (marijuana, tetrahydrocannabinol, hashish); inhalants
(nitrous oxide, amyl nitrite, butyl nitrite, chlorohydrocarbons,
hydrocarbons); cocaine (crack cocaine); stimulants (amphetamines,
methamphetamines, Ritalin, Cylert, Preludin, Didrex, PreState,
Voranil, Sandrex, Plegine); depressants (barbituates, methaqualone,
tranquilizers such as Valium, Librium, Miltown, Serax, Equanil,
Tranxene); hallucinogens (phencyclidine, lysergic acid, mescaline,
peyote, psilocybin); narcotics (heroin, codeine, morphine, opium,
meperidine, Percocet, Percodan, Tussionex, Fentanyl, Darvon,
Talwin, Lomotil); designer drugs (analogs of fentanyl, meperidine,
amphetamines, methamphetamines, and phencyclidine, for example,
Ecstasy); anabolic steroids; and nicotine. The metabolic products
of drugs and pharmaceutical compositions are also contemplated
analytes. Analytes such as neurochemicals and other chemicals
generated within the body may also be analyzed, such as, for
example, ascorbic acid, uric acid, dopamine, noradrenaline,
3-methoxytyramine (3MT), 3,4-Dihydroxyphenylacetic acid (DOPAC),
Homovanillic acid (HVA), 5-Hydroxytryptamine (5HT), and
5-Hydroxyindoleacetic acid (FHIAA).
The term "continuous glucose sensor" as used herein is a broad
term, and is to be given its ordinary and customary meaning to a
person of ordinary skill in the art (and it is not to be limited to
a special or customized meaning), and refers without limitation to
a device that continuously or continually measures glucose
concentration, for example, at time intervals ranging from
fractions of a second up to, for example, 1, 2, or 5 minutes, or
longer. It should be understood that continuous glucose sensors can
continually measure glucose concentration without requiring user
initiation and/or interaction for each measurement, such as
described with reference to U.S. Pat. No. 6,001,067, for
example.
The phrase "continuous glucose sensing" as used herein is a broad
term, and is to be given its ordinary and customary meaning to a
person of ordinary skill in the art (and it is not to be limited to
a special or customized meaning), and refers without limitation to
the period in which monitoring of plasma glucose concentration is
continuously or continually performed, for example, at time
intervals ranging from fractions of a second up to, for example, 1,
2, or 5 minutes, or longer.
The term "biological sample" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a sample
of a host body, for example, blood, interstitial fluid, spinal
fluid, saliva, urine, tears, sweat, tissue, and the like.
The term "host" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to plants or animals, for
example humans.
The term "biointerface membrane" as used herein is a broad term,
and is to be given its ordinary and customary meaning to a person
of ordinary skill in the art (and it is not to be limited to a
special or customized meaning), and refers without limitation to a
permeable or semi-permeable membrane that can include one or more
domains and is typically constructed of materials of a few microns
thickness or more, which can be placed over the sensing region to
keep host cells (for example, macrophages) from gaining proximity
to, and thereby damaging the membrane system or forming a barrier
cell layer and interfering with the transport of glucose across the
tissue-device interface.
The term "membrane system" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a
permeable or semi-permeable membrane that can be comprised of one
or more domains and is typically constructed of materials of a few
microns thickness or more, which may be permeable to oxygen and are
optionally permeable to glucose. In one example, the membrane
system comprises an immobilized glucose oxidase enzyme, which
enables an electrochemical reaction to occur to measure a
concentration of glucose.
The term "domain" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to regions of a
membrane that can be layers, uniform or non-uniform gradients (for
example, anisotropic), functional aspects of a material, or
provided as portions of the membrane.
The term "copolymer" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to polymers
having two or more different repeat units and includes copolymers,
terpolymers, tetrapolymers, and the like.
The term "sensing region" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to the region of
a monitoring device responsible for the detection of a particular
analyte. In one embodiment, the sensing region generally comprises
a non-conductive body, at least one electrode, a reference
electrode and a optionally a counter electrode passing through and
secured within the body forming an electrochemically reactive
surface at one location on the body and an electronic connection at
another location on the body, and a membrane system affixed to the
body and covering the electrochemically reactive surface. In
another embodiment, the sensing region generally comprises a
non-conductive body, a working electrode (anode), a reference
electrode (optionally can be remote from the sensing region), an
insulator disposed therebetween, and a multi-domain membrane
affixed to the body and covering the electrochemically reactive
surfaces of the working and optionally reference electrodes.
The term "electrochemically reactive surface" as used herein is a
broad term, and is to be given its ordinary and customary meaning
to a person of ordinary skill in the art (and it is not to be
limited to a special or customized meaning), and refers without
limitation to the surface of an electrode where an electrochemical
reaction takes place. In one embodiment, a working electrode
measures hydrogen peroxide creating a measurable electronic
current.
The term "electrochemical cell" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a device
in which chemical energy is converted to electrical energy. Such a
cell typically consists of two or more electrodes held apart from
each other and in contact with an electrolyte solution. Connection
of the electrodes to a source of direct electric current renders
one of them negatively charged and the other positively charged.
Positive ions in the electrolyte migrate to the negative electrode
(cathode) and there combine with one or more electrons, losing part
or all of their charge and becoming new ions having lower charge or
neutral atoms or molecules; at the same time, negative ions migrate
to the positive electrode (anode) and transfer one or more
electrons to it, also becoming new ions or neutral particles. The
overall effect of the two processes is the transfer of electrons
from the negative ions to the positive ions, a chemical
reaction.
The term "electrode" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a conductor
through which electricity enters or leaves something such as a
battery or a piece of electrical equipment. In one embodiment, the
electrodes are the metallic portions of a sensor (e.g.,
electrochemically reactive surfaces) that are exposed to the
extracellular milieu, for detecting the analyte. In some
embodiments, the term electrode includes the conductive wires or
traces that electrically connect the electrochemically reactive
surface to connectors (for connecting the sensor to electronics) or
to the electronics.
The term "enzyme" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a protein or
protein-based molecule that speeds up a chemical reaction occurring
in a living thing. Enzymes may act as catalysts for a single
reaction, converting a reactant (also called an analyte herein)
into a specific product. In one exemplary embodiment of a glucose
oxidase-based glucose sensor, an enzyme, glucose oxidase (GOX) is
provided to react with glucose (the analyte) and oxygen to form
hydrogen peroxide.
The term "co-analyte" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a molecule
required in an enzymatic reaction to react with the analyte and the
enzyme to form the specific product being measured. In one
exemplary embodiment of a glucose sensor, an enzyme, glucose
oxidase (GOX) is provided to react with glucose and oxygen (the
co-analyte) to form hydrogen peroxide.
The term "constant analyte" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to an analyte
that remains relatively constant over a time period, for example
over an hour to a day as compared to other variable analytes. For
example, in a person with diabetes, oxygen and urea may be
relatively constant analytes in particular tissue compartments
relative to glucose, which is known to oscillate between about 40
and 400 mg/dL during a 24-hour cycle. Although analytes such as
oxygen and urea are known to oscillate to a lesser degree, for
example due to physiological processes in a host, they are
substantially constant, relative to glucose, and can be digitally
filtered, for example low pass filtered, to minimize or eliminate
any relatively low amplitude oscillations. Constant analytes other
than oxygen and urea are also contemplated.
The term "proximal" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to near to a
point of reference such as an origin or a point of attachment. For
example, in some embodiments of a membrane system that covers an
electrochemically reactive surface, the electrolyte domain is
located more proximal to the electrochemically reactive surface
than the resistance domain.
The term "distal" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to spaced
relatively far from a point of reference, such as an origin or a
point of attachment. For example, in some embodiments of a membrane
system that covers an electrochemically reactive surface, a
resistance domain is located more distal to the electrochemically
reactive surfaces than the electrolyte domain.
The term "substantially" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a sufficient
amount that provides a desired function. For example, the
interference domain of the preferred embodiments is configured to
resist a sufficient amount of interfering species such that
tracking of glucose levels can be achieved, which may include an
amount greater than 50 percent, an amount greater than 60 percent,
an amount greater than 70 percent, an amount greater than 80
percent, or an amount greater than 90 percent of interfering
species.
The term "computer" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to machine that
can be programmed to manipulate data.
The term "modem" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to an electronic device for
converting between serial data from a computer and an audio signal
suitable for transmission over a telecommunications connection to
another modem.
The terms "processor module" and "microprocessor" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to a computer system, state machine, processor,
or the like designed to perform arithmetic and logic operations
using logic circuitry that responds to and processes the basic
instructions that drive a computer.
The term "ROM" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to read-only memory, which
is a type of data storage device manufactured with fixed contents.
ROM is broad enough to include EEPROM, for example, which is
electrically erasable programmable read-only memory (ROM).
The term "RAM" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to a data storage device
for which the order of access to different locations does not
affect the speed of access. RAM is broad enough to include SRAM,
for example, which is static random access memory that retains data
bits in its memory as long as power is being supplied.
The term "A/D Converter" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to hardware
and/or software that converts analog electrical signals into
corresponding digital signals.
The term "RF transceiver" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a radio
frequency transmitter and/or receiver for transmitting and/or
receiving signals.
The terms "raw data stream" and "data stream" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to an analog or digital signal directly related
to the analyte concentration measured by the analyte sensor. In one
example, the raw data stream is digital data in "counts" converted
by an A/D converter from an analog signal (for example, voltage or
amps) representative of an analyte concentration. The terms broadly
encompass a plurality of time spaced data points from a
substantially continuous analyte sensor, which comprises individual
measurements taken at time intervals ranging from fractions of a
second up to, for example, 1, 2, or 5 minutes or longer. In some
embodiments, raw data includes one or more values (e.g., digital
value) representative of the current flow integrated over time
(e.g., integrated value), for example, using a charge counting
device, or the like.
The term "counts" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to a unit of
measurement of a digital signal. In one example, a raw data stream
measured in counts is directly related to a voltage (for example,
converted by an A/D converter), which is directly related to
current from a working electrode.
The term "electronic circuitry" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to the
components (for example, hardware and/or software) of a device
configured to process data. In the case of an analyte sensor, the
data includes biological information obtained by a sensor regarding
the concentration of the analyte in a biological fluid. U.S. Pat.
Nos. 4,757,022, 5,497,772 and 4,787,398, which are hereby
incorporated by reference in their entirety, describe suitable
electronic circuits that can be utilized with devices of certain
embodiments.
The term "potentiostat" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to an electrical
system that applies a potential between the working and reference
electrodes of a two- or three-electrode cell at a preset value and
measures the current flow through the working electrode. Typically,
the potentiostat forces whatever current is necessary to flow
between the working and reference or counter electrodes to keep the
desired potential, as long as the needed cell voltage and current
do not exceed the compliance limits of the potentiostat.
The terms "operably connected" and "operably linked" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to one or more components being linked to
another component(s) in a manner that allows transmission of
signals between the components. For example, one or more electrodes
can be used to detect the amount of glucose in a sample and convert
that information into a signal; the signal can then be transmitted
to an electronic circuit. In this case, the electrode is "operably
linked" to the electronic circuit. These terms are broad enough to
include wired and wireless connectivity.
The term "smoothing" and "filtering" as used herein are broad
terms, and are to be given their ordinary and customary meaning to
a person of ordinary skill in the art (and they are not to be
limited to a special or customized meaning), and refer without
limitation to modification of a set of data to make it smoother and
more continuous and remove or diminish outlying points, for
example, by performing a moving average of the raw data stream.
The term "algorithm" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to the
computational processes (for example, programs) involved in
transforming information from one state to another, for example
using computer processing.
The term "regression" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to finding a
line in which a set of data has a minimal measurement (for example,
deviation) from that line. Regression can be linear, non-linear,
first order, second order, and so forth. One example of regression
is least squares regression.
The term "pulsed amperometric detection" as used herein is a broad
term, and is to be given its ordinary and customary meaning to a
person of ordinary skill in the art (and it is not to be limited to
a special or customized meaning), and refers without limitation to
an electrochemical flow cell and a controller, which applies the
potentials and monitors current generated by the electrochemical
reactions. The cell can include one or multiple working electrodes
at different applied potentials. Multiple electrodes can be
arranged so that they face the chromatographic flow independently
(parallel configuration), or sequentially (series
configuration).
The term "calibration" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to the
relationship and/or the process of determining the relationship
between the sensor data and corresponding reference data, which may
be used to convert sensor data into meaningful values substantially
equivalent to the reference. In some embodiments, namely in
continuous analyte sensors, calibration may be updated or
recalibrated over time if changes in the relationship between the
sensor and reference data occur, for example due to changes in
sensitivity, baseline, transport, metabolism, or the like.
The term "sensor analyte values" and "sensor data" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to data received from a continuous analyte
sensor, including one or more time-spaced sensor data points.
The term "reference analyte values" and "reference data" as used
herein are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and
they are not to be limited to a special or customized meaning), and
refer without limitation to data from a reference analyte monitor,
such as a blood glucose meter, or the like, including one or more
reference data points. In some embodiments, the reference glucose
values are obtained from a self-monitored blood glucose (SMBG) test
(for example, from a finger or forearm blood test) or an YSI
(Yellow Springs Instruments) test, for example.
The term "matched data pairs" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to reference
data (for example, one or more reference analyte data points)
matched with substantially time corresponding sensor data (for
example, one or more sensor data points).
The terms "interferants" and "interfering species" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to effects and/or species that interfere with
the measurement of an analyte of interest in a sensor to produce a
signal that does not accurately represent the analyte measurement.
In one example of an electrochemical sensor, interfering species
are compounds with an oxidation potential that overlaps with the
analyte to be measured, producing a false positive signal. In
another example of an electrochemical sensor, interfering species
are substantially non-constant compounds (e.g., the concentration
of an interfering species fluctuates over time). Interfering
species include but are not limited to compounds with electroactive
acidic, amine or sulfhydryl groups, urea, lactic acid, phosphates,
citrates, peroxides, amino acids, amino acid precursors or
break-down products, nitric oxide (NO), NO-donors, NO-precursors,
acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,
dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa, salicylate,
tetracycline, tolazamide, tolbutamide, triglycerides, and uric acid
electroactive species produced during cell metabolism and/or wound
healing, electroactive species that arise during body pH changes
and the like.
The term "bifunctional" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to having or
serving two functions. For example, in a needle-type analyte
sensor, a metal wire is bifunctional because it provides structural
support and acts as an electrical conductor.
The term "function" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to an action or
use for which something is suited or designed.
The term "electrical conductor" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning) and refers without limitation to materials that
contain movable charges of electricity. When an electric potential
difference is impressed across separate points on a conductor, the
mobile charges within the conductor are forced to move, and an
electric current between those points appears in accordance with
Ohm's law.
Accordingly, the term "electrical conductance" as used herein is a
broad term, and is to be given its ordinary and customary meaning
to a person of ordinary skill in the art (and is not to be limited
to a special or customized meaning) and refers without limitation
to the propensity of a material to behave as an electrical
conductor. In some embodiments, the term refers to a sufficient
amount of electrical conductance (e.g., material property) to
provide a necessary function (electrical conduction).
The terms "insulative properties," "electrical insulator" and
"insulator" as used herein are broad terms, and are to be given
their ordinary and customary meaning to a person of ordinary skill
in the art (and is not to be limited to a special or customized
meaning) and refers without limitation to the tendency of materials
that lack mobile charges to prevent movement of electrical charges
between two points. In one exemplary embodiment, an electrically
insulative material may be placed between two electrically
conductive materials, to prevent movement of electricity between
the two electrically conductive materials. In some embodiments, the
terms refer to a sufficient amount of insulative property (e.g., of
a material) to provide a necessary function (electrical
insulation). The terms "insulator" and "non-conductive material"
can be used interchangeably herein.
The term "structural support" as used herein is a broad term, and
is to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning) and refers without limitation to the tendency
of a material to keep the sensor's structure stable or in place.
For example, structural support can include "weight bearing" as
well as the tendency to hold the parts or components of a whole
structure together. A variety of materials can provide "structural
support" to the sensor.
The term "diffusion barrier" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning) and refers without limitation to something that
obstructs the random movement of compounds, species, atoms,
molecules, or ions from one site in a medium to another. In some
embodiments, a diffusion barrier is structural, such as a wall that
separates two working electrodes and substantially prevents
diffusion of a species from one electrode to the other. In some
embodiments, a diffusion barrier is spatial, such as separating
working electrodes by a distance sufficiently large enough to
substantially prevent a species at a first electrode from affecting
a second electrode. In other embodiments, a diffusion barrier can
be temporal, such as by turning the first and second working
electrodes on and off, such that a reaction at a first electrode
will not substantially affect the function of the second
electrode.
The terms "integral," "integrally," "integrally formed,"
"integrally incorporated," "unitary" and "composite" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and they are not
to be limited to a special or customized meaning), and refer
without limitation to the condition of being composed of essential
parts or elements that together make a whole. The parts are
essential for completeness of the whole. In one exemplary
embodiment, at least a portion (e.g., the in vivo portion) of the
sensor is formed from at least one platinum wire at least partially
covered with an insulative coating, which is at least partially
helically wound with at least one additional wire, the exposed
electroactive portions of which are covered by a membrane system
(see description of FIG. 1B or 9B); in this exemplary embodiment,
each element of the sensor is formed as an integral part of the
sensor (e.g., both functionally and structurally).
The term "coaxial" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to having a
common axis, having coincident axes or mounted on concentric
shafts.
The term "twisted" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to united by
having one part or end turned in the opposite direction to the
other, such as, but not limited to the twisted strands of fiber in
a string, yarn, or cable.
The term "helix" as used herein is a broad term, and is to be given
its ordinary and customary meaning to a person of ordinary skill in
the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to a spiral or coil, or
something in the form of a spiral or coil (e.g. a corkscrew or a
coiled spring). In one example, a helix is a mathematical curve
that lies on a cylinder or cone and makes a constant angle with the
straight lines lying in the cylinder or cone. A "double helix" is a
pair of parallel helices intertwined about a common axis, such as
but not limited to that in the structure of DNA.
The term "in vivo portion" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a portion
of a device that is to be implanted or inserted into the host. In
one exemplary embodiment, an in vivo portion of a transcutaneous
sensor is a portion of the sensor that is inserted through the
host's skin and resides within the host.
The terms "background," "baseline," and "noise" as used herein are
broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and is not to be
limited to a special or customized meaning), and refer without
limitation to a component of an analyte sensor signal that is not
related to the analyte concentration. In one example of a glucose
sensor, the background is composed substantially of signal
contribution due to factors other than glucose (for example,
interfering species, non-reaction-related hydrogen peroxide, or
other electroactive species with an oxidation potential that
overlaps with hydrogen peroxide). In some embodiments wherein a
calibration is defined by solving for the equation y=mx+b, the
value of b represents the background of the signal. In general, the
background (noise) comprises components related to constant and
non-constant factors.
The term "constant noise" and "constant background" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and it is not to
be limited to a special or customized meaning), and refer without
limitation to the component of the background signal that remains
relatively constant over time. For example, certain electroactive
compounds found in the human body are relatively constant factors
(e.g., baseline of the host's physiology) and do not significantly
adversely affect accuracy of the calibration of the glucose
concentration (e.g., they can be relatively constantly eliminated
using the equation y=mx+b). In some circumstances, constant
background noise can slowly drift over time (e.g., increases or
decreases), however this drift need not adversely affect the
accuracy of a sensor, for example, because a sensor can be
calibrated and re-calibrated and/or the drift measured and
compensated for.
The term "non-constant noise" or non-constant background" as used
herein are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and it
is not to be limited to a special or customized meaning), and refer
without limitation to a component of the background signal that is
relatively non-constant, for example, transient and/or
intermittent. For example, certain electroactive compounds, are
relatively non-constant (e.g., intermittent interferents due to the
host's ingestion, metabolism, wound healing, and other mechanical,
chemical and/or biochemical factors), which create intermittent
(e.g., non-constant) "noise" on the sensor signal that can be
difficult to "calibrate out" using a standard calibration equations
(e.g., because the background of the signal does not remain
constant).
The terms "inactive enzyme" or "inactivated enzyme" as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and it is not to
be limited to a special or customized meaning), and refer without
limitation to an enzyme (e.g., glucose oxidase, GOx) that has been
rendered inactive (e.g., "killed" or "dead") and has no enzymatic
activity. Enzymes can be inactivated using a variety of techniques
known in the art, such as but not limited to heating, freeze-thaw,
denaturing in organic solvent, acids or bases, cross-linking,
genetically changing enzymatically critical amino acids, and the
like. In some embodiments, a solution containing active enzyme can
be applied to the sensor, and the applied enzyme subsequently
inactivated by heating or treatment with an inactivating
solvent.
The term "non-enzymatic" as used herein is a broad term, and is to
be given their ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a lack of
enzyme activity. In some embodiments, a "non-enzymatic" membrane
portion contains no enzyme; while in other embodiments, the
"non-enzymatic" membrane portion contains inactive enzyme. In some
embodiments, an enzyme solution containing inactive enzyme or no
enzyme is applied.
The term "GOx" as used herein is a broad term, and is to be given
their ordinary and customary meaning to a person of ordinary skill
in the art (and it is not to be limited to a special or customized
meaning), and refers without limitation to the enzyme Glucose
Oxidase (e.g., GOx is an abbreviation).
The term "comprising" as used herein is synonymous with
"including," "containing," or "characterized by," and is inclusive
or open-ended and does not exclude additional, unrecited elements
or method steps.
All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification and claims are
to be understood as being modified in all instances by the term
"about." Accordingly, unless indicated to the contrary, the
numerical parameters set forth in the specification and attached
claims are approximations that can vary depending upon the desired
properties sought to be obtained by the present invention. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of the claims, each numerical
parameter should be construed in light of the number of significant
digits and ordinary rounding approaches.
Overview
The preferred embodiments provide a continuous analyte sensor that
measures a concentration of the analyte of interest or a substance
indicative of the concentration or presence of the analyte. In some
embodiments, the analyte sensor is an invasive, minimally invasive,
or non-invasive device, for example a subcutaneous, transdermal, or
intravascular device. In some embodiments, the analyte sensor may
analyze a plurality of intermittent biological samples. The analyte
sensor may use any method of analyte-measurement, including
enzymatic, chemical, physical, electrochemical, spectrophotometric,
polarimetric, calorimetric, radiometric, or the like.
In general, analyte sensors provide at least one working electrode
and at least one reference electrode, which are configured to
measure a signal associated with a concentration of the analyte in
the host, such as described in more detail below, and as
appreciated by one skilled in the art. The output signal is
typically a raw data stream that is used to provide a useful value
of the measured analyte concentration in a host to the patient or
doctor, for example. However, the analyte sensors of the preferred
embodiments may further measure at least one additional signal. For
example, in some embodiments, the additional signal is associated
with the baseline and/or sensitivity of the analyte sensor, thereby
enabling monitoring of baseline and/or sensitivity changes that may
occur in a continuous analyte sensor over time.
In general, continuous analyte sensors define a relationship
between sensor-generated measurements (for example, current in nA
or digital counts after A/D conversion) and a reference measurement
(for example, mg/dL or mmol/L) that are meaningful to a user (for
example, patient or doctor). In the case of an implantable
enzyme-based electrochemical glucose sensor, the sensing mechanism
generally depends on phenomena that are linear with glucose
concentration, for example: (1) diffusion of glucose through a
membrane system (for example, biointerface membrane and membrane
system) situated between implantation site and the electrode
surface, (2) an enzymatic reaction within the membrane system (for
example, membrane system), and (3) diffusion of the H.sub.2O.sub.2
to the sensor. Because of this linearity, calibration of the sensor
can be understood by solving an equation: y=mx+b where y represents
the sensor signal (counts), x represents the estimated glucose
concentration (mg/dL), m represents the sensor sensitivity to
glucose (counts/mg/dL), and b represents the baseline signal
(counts). Because both sensitivity m and baseline (background) b
change over time in vivo, calibration has conventionally required
at least two independent, matched data pairs (x.sub.1, y.sub.1;
x.sub.2, y.sub.2) to solve for m and b and thus allow glucose
estimation when only the sensor signal, y is available. Matched
data pairs can be created by matching reference data (for example,
one or more reference glucose data points from a blood glucose
meter, or the like) with substantially time corresponding sensor
data (for example, one or more glucose sensor data points) to
provide one or more matched data pairs, such as described in
co-pending U.S. Publication No. US-2005-0027463-A1.
Accordingly, in some embodiments, the sensing region is configured
to measure changes in sensitivity of the analyte sensor over time,
which can be used to trigger calibration, update calibration, avoid
inaccurate calibration (for example, calibration during unstable
periods), and/or trigger filtering of the sensor data. Namely, the
analyte sensor is configured to measure a signal associated with a
non-analyte constant in the host. Preferably, the non-analyte
constant signal is measured beneath the membrane system on the
sensor. In one example of a glucose sensor, a non-glucose constant
that can be measured is oxygen, wherein a measured change in oxygen
transport is indicative of a change in the sensitivity of the
glucose signal, which can be measured by switching the bias
potential of the working electrode, an auxiliary oxygen-measuring
electrode, an oxygen sensor, or the like, as described in more
detail elsewhere herein.
Alternatively or additionally, in some embodiments, the sensing
region is configured to measure changes in the amount of background
noise (e.g., baseline) in the signal, which can be used to trigger
calibration, update calibration, avoid inaccurate calibration (for
example, calibration during unstable periods), and/or trigger
filtering of the sensor data. In one example of a glucose sensor,
the baseline is composed substantially of signal contribution due
to factors other than glucose (for example, interfering species,
non-reaction-related hydrogen peroxide, or other electroactive
species with an oxidation potential that overlaps with hydrogen
peroxide). Namely, the glucose sensor is configured to measure a
signal associated with the baseline (all non-glucose related
current generated) measured by sensor in the host. In some
embodiments, an auxiliary electrode located beneath a non-enzymatic
portion of the membrane system is used to measure the baseline
signal. In some embodiments, the baseline signal is subtracted from
the glucose signal (which includes the baseline) to obtain the
signal contribution substantially only due to glucose. Subtraction
may be accomplished electronically in the sensor using a
differential amplifier, digitally in the receiver, and/or otherwise
in the hardware or software of the sensor or receiver as is
appreciated by one skilled in the art, and as described in more
detail elsewhere herein.
One skilled in the art appreciates that the above-described
sensitivity and baseline signal measurements can be combined to
benefit from both measurements in a single analyte sensor.
Preferred Sensor Components
In general, sensors of the preferred embodiments describe a variety
of sensor configurations, wherein each sensor generally comprises
two or more working electrodes, a reference and/or counter
electrode, an insulator, and a membrane system. In general, the
sensors can be configured to continuously measure an analyte in a
biological sample, for example, in subcutaneous tissue, in a host's
blood flow, and the like. Although a variety of exemplary
embodiments are shown, one skilled in the art appreciates that the
concepts and examples here can be combined, reduced, substituted,
or otherwise modified in accordance with the teachings of the
preferred embodiments and/or the knowledge of one skilled in the
art.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A
through 9B, and 11) includes a first working electrode, wherein the
working electrode is formed from known materials. In some
embodiments, each electrode is formed from a fine wire with a
diameter of from about 0.001 or less to about 0.010 inches or more,
for example, and is formed from, e.g., a plated insulator, a plated
wire, or bulk electrically conductive material. In preferred
embodiments, the working electrode comprises a wire formed from a
conductive material, such as platinum, platinum-iridium, palladium,
graphite, gold, carbon, conductive polymer, alloys, or the like.
Although the electrodes can by formed by a variety of manufacturing
techniques (bulk metal processing, deposition of metal onto a
substrate, and the like), it can be advantageous to form the
electrodes from plated wire (e.g., platinum on steel wire) or bulk
metal (e.g., platinum wire). It is believed that electrodes formed
from bulk metal wire provide superior performance (e.g., in
contrast to deposited electrodes), including increased stability of
assay, simplified manufacturability, resistance to contamination
(e.g., which can be introduced in deposition processes), and
improved surface reaction (e.g., due to purity of material) without
peeling or delamination.
Preferably, the working electrode is configured to measure the
concentration of an analyte. In an enzymatic electrochemical sensor
for detecting glucose, for example, the working electrode measures
the hydrogen peroxide produced by an enzyme catalyzed reaction of
the analyte being detected and creates a measurable electronic
current. For example, in the detection of glucose wherein glucose
oxidase produces hydrogen peroxide as a byproduct, hydrogen
peroxide (H.sub.2O.sub.2) reacts with the surface of the working
electrode producing two protons (2H.sup.+), two electrons
(2e.sup.-) and one molecule of oxygen (O.sub.2), which produces the
electronic current being detected.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A
through 9B, and 11) includes at least one additional working
electrode configured to measure a baseline (e.g., background noise)
signal, to measure another analyte (e.g., oxygen), to generate
oxygen, and/or as a transport-measuring electrode, all of which are
described in more detail elsewhere herein. In general, the
additional working electrode(s) can be formed as described with
reference to the first working electrode. In one embodiment, the
auxiliary (additional) working electrode is configured to measure a
background signal, including constant and non-constant analyte
signal components.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, and
7A through 9B) includes a reference and/or counter electrode. In
general, the reference electrode has a configuration similar to
that described elsewhere herein with reference to the first working
electrode, however may be formed from materials, such as silver,
silver/silver chloride, calomel, and the like. In some embodiments,
the reference electrode is integrally formed with the one or more
working electrodes, however other configurations are also possible
(e.g., remotely located on the host's skin, or otherwise in bodily
fluid contact). In some exemplary embodiments (e.g., FIGS. 1B and
9B, the reference electrode is helically wound around other
component(s) of the sensor system. In some alternative embodiments,
the reference electrode is disposed remotely from the sensor, such
as but not limited to on the host's skin, as described herein.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A
through 9B, and 11) includes an insulator (e.g., non-conductive
material) or similarly functional component. In some embodiments,
one or more electrodes are covered with an insulating material, for
example, a non-conductive polymer. Dip-coating, spray-coating,
vapor-deposition, or other coating or deposition techniques can be
used to deposit the insulating material on the electrode(s). In
some embodiments, the insulator is a separate component of the
system (e.g., see FIG. 7E) and can be formed as is appreciated by
one skilled in the art. In one embodiment, the insulating material
comprises parylene, which can be an advantageous polymer coating
for its strength, lubricity, and electrical insulation properties.
Generally, parylene is produced by vapor deposition and
polymerization of para-xylylene (or its substituted derivatives).
In alternative embodiments, any suitable insulating material can be
used, for example, fluorinated polymers, polyethyleneterephthalate,
polyurethane, polyimide, other nonconducting polymers, or the like.
Glass or ceramic materials can also be employed. Other materials
suitable for use include surface energy modified coating systems
such as are marketed under the trade names AMC18, AMC148, AMC141,
and AMC321 by Advanced Materials Components Express of Bellefonte,
PA.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A
through 9B, and 11) includes exposed electroactive area(s). In
embodiments wherein an insulator is disposed over one or more
electrodes, a portion of the coated electrode(s) can be stripped or
otherwise removed, for example, by hand, excimer lasing, chemical
etching, laser ablation, grit-blasting (e.g., with sodium
bicarbonate or other suitable grit), and the like, to expose the
electroactive surfaces. Alternatively, a portion of the electrode
can be masked prior to depositing the insulator in order to
maintain an exposed electroactive surface area. In one exemplary
embodiment, grit blasting is implemented to expose the
electroactive surfaces, preferably utilizing a grit material that
is sufficiently hard to ablate the polymer material, while being
sufficiently soft so as to minimize or avoid damage to the
underlying metal electrode (e.g., a platinum electrode). Although a
variety of "grit" materials can be used (e.g., sand, talc, walnut
shell, ground plastic, sea salt, and the like), in some preferred
embodiments, sodium bicarbonate is an advantageous grit-material
because it is sufficiently hard to ablate, a coating (e.g.,
parylene) without damaging, an underlying conductor (e.g.,
platinum). One additional advantage of sodium bicarbonate blasting
includes its polishing action on the metal as it strips the polymer
layer, thereby eliminating a cleaning step that might otherwise be
necessary. In some embodiments, the tip (e.g., end) of the sensor
is cut to expose electroactive surface areas, without a need for
removing insulator material from sides of insulated electrodes. In
general, a variety of surfaces and surface areas can be
exposed.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, 7A
through 9B, and 11) includes a membrane system. Preferably, a
membrane system is deposited over at least a portion of the
electroactive surfaces of the sensor (working electrode(s) and
optionally reference electrode) and provides protection of the
exposed electrode surface from the biological environment,
diffusion resistance (limitation) of the analyte if needed, a
catalyst for enabling an enzymatic reaction, limitation or blocking
of interferents, and/or hydrophilicity at the electrochemically
reactive surfaces of the sensor interface. Some examples of
suitable membrane systems are described in U.S. Publication No.
US-2005-0245799-A1.
In general, the membrane system includes a plurality of domains,
for example, one or more of an electrode domain 24, an optional
interference domain 26, an enzyme domain 28 (for example, including
glucose oxidase), and a resistance domain 30, as shown in FIGS. 2A
and 2B, and can include a high oxygen solubility domain, and/or a
bioprotective domain (not shown), such as is described in more
detail in U.S. Publication No. US-2005-0245799-A1, and such as is
described in more detail below. The membrane system can be
deposited on the exposed electroactive surfaces using known thin
film techniques (for example, vapor deposition, spraying,
electro-depositing, dipping, or the like). In alternative
embodiments, however, other vapor deposition processes (e.g.,
physical and/or chemical vapor deposition processes) can be useful
for providing one or more of the insulating and/or membrane layers,
including ultrasonic vapor deposition, electrostatic deposition,
evaporative deposition, deposition by sputtering, pulsed laser
deposition, high velocity oxygen fuel deposition, thermal
evaporator deposition, electron beam evaporator deposition,
deposition by reactive sputtering molecular beam epitaxy,
atmospheric pressure chemical vapor deposition (CVD), atomic layer
CVD, hot wire CVD, low-pressure CVD, microwave plasma-assisted CVD,
plasma-enhanced CVD, rapid thermal CVD, remote plasma-enhanced CVD,
and ultra-high vacuum CVD, for example. However, the membrane
system can be disposed over (or deposited on) the electroactive
surfaces using any known method, as will be appreciated by one
skilled in the art.
In some embodiments, one or more domains of the membrane systems
are formed from materials such as silicone,
polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,
polyolefin, polyester, polycarbonate, biostable
polytetrafluoroethylene, homopolymers, copolymers, terpolymers of
polyurethanes, polypropylene (PP), polyvinylchloride (PVC),
polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT),
polymethylmethacrylate (PMMA), polyether ether ketone (PEEK),
polyurethanes, cellulosic polymers, polysulfones and block
copolymers thereof including, for example, di-block, tri-block,
alternating, random and graft copolymers. U.S. Publication No.
US-2005-0245799-A1 describes biointerface and membrane system
configurations and materials that may be applied to the preferred
embodiments.
Electrode Domain
In selected embodiments, the membrane system comprises an electrode
domain 24 (FIGS. 2A-2B). The electrode domain is provided to ensure
that an electrochemical reaction occurs between the electroactive
surfaces of the working electrode and the reference electrode, and
thus the electrode domain is preferably situated more proximal to
the electroactive surfaces than the interference and/or enzyme
domain. Preferably, the electrode domain includes a coating that
maintains a layer of water at the electrochemically reactive
surfaces of the sensor. In other words, the electrode domain is
present to provide an environment between the surfaces of the
working electrode and the reference electrode, which facilitates an
electrochemical reaction between the electrodes. For example, a
humectant in a binder material can be employed as an electrode
domain; this allows for the full transport of ions in the aqueous
environment. The electrode domain can also assist in stabilizing
the operation of the sensor by accelerating electrode start-up and
drifting problems caused by inadequate electrolyte. The material
that forms the electrode domain can also provide an environment
that protects against pH-mediated damage that can result from the
formation of a large pH gradient due to the electrochemical
activity of the electrodes.
In one embodiment, the electrode domain includes a flexible,
water-swellable, hydrogel film having a "dry film" thickness of
from about 0.05 micron or less to about 20 microns or more, more
preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,
0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and
more preferably still from about 2, 2.5 or 3 microns to about 3.5,
4, 4.5, or 5 microns. "Dry film" thickness refers to the thickness
of a cured film cast from a coating formulation by standard coating
techniques.
In certain embodiments, the electrode domain is formed of a curable
mixture of a urethane polymer and a hydrophilic polymer.
Particularly preferred coatings are formed of a polyurethane
polymer having carboxylate or hydroxyl functional groups and
non-ionic hydrophilic polyether segments, wherein the polyurethane
polymer is crosslinked with a water-soluble carbodiimide (e.g.,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the
presence of polyvinylpyrrolidone and cured at a moderate
temperature of about 50.degree. C.
In some preferred embodiments, the electrode domain is formed from
a hydrophilic polymer such as polyvinylpyrrolidone (PVP). An
electrode domain formed from PVP has been shown to reduce break-in
time of analyte sensors; for example, a glucose sensor utilizing a
cellulosic-based interference domain such as described in more
detail below.
Preferably, the electrode domain is deposited by vapor deposition,
spray coating, dip coating, or other thin film techniques on the
electroactive surfaces of the sensor. In one preferred embodiment,
the electrode domain is formed by dip-coating the electroactive
surfaces in an electrode layer solution and curing the domain for a
time of from about 15 minutes to about 30 minutes at a temperature
of from about 40.degree. C. to about 55.degree. C. (and can be
accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments
wherein dip-coating is used to deposit the electrode domain, a
preferred insertion rate of from about 1 to about 3 inches per
minute into the electrode layer solution, with a preferred dwell
time of from about 0.5 to about 2 minutes in the electrode layer
solution, and a preferred withdrawal rate of from about 0.25 to
about 2 inches per minute from the electrode layer solution provide
a functional coating. However, values outside of those set forth
above can be acceptable or even desirable in certain embodiments,
for example, depending upon solution viscosity and solution surface
tension, as is appreciated by one skilled in the art. In one
embodiment, the electroactive surfaces of the electrode system are
dip-coated one time (one layer) and cured at 50.degree. C. under
vacuum for 20 minutes.
Although an independent electrode domain is described herein, in
some embodiments sufficient hydrophilicity can be provided in the
interference domain and/or enzyme domain (the domain adjacent to
the electroactive surfaces) so as to provide for the full transport
of ions in the aqueous environment (e.g. without a distinct
electrode domain). In these embodiments, an electrode domain is not
necessary.
Interference Domain
Interferents are molecules or other species that are reduced or
oxidized at the electrochemically reactive surfaces of the sensor,
either directly or via an electron transfer agent, to produce a
false positive analyte signal. In preferred embodiments, an
optional interference domain 26 is provided that substantially
restricts, resists, or blocks the flow of one or more interfering
species (FIGS. 2A-2B). Some known interfering species for a glucose
sensor, as described in more detail above, include acetaminophen,
ascorbic acid, bilirubin, cholesterol, creatinine, dopamine,
ephedrine, ibuprofen, L-dopa, methyldopa, salicylate, tetracycline,
tolazamide, tolbutamide, triglycerides, and uric acid. In general,
the interference domain of the preferred embodiments is less
permeable to one or more of the interfering species than to the
analyte, e.g., glucose.
In one embodiment, the interference domain is formed from one or
more cellulosic derivatives. In general, cellulosic derivatives
include polymers such as cellulose acetate, cellulose acetate
butyrate, 2-hydroxyethyl cellulose, cellulose acetate phthalate,
cellulose acetate propionate, cellulose acetate trimellitate, and
the like.
In one preferred embodiment, the interference domain is formed from
cellulose acetate butyrate. Cellulose acetate butyrate with a
molecular weight of about 10,000 daltons to about 75,000 daltons,
preferably from about 15,000, 20,000, or 25,000 daltons to about
50,000, 55,000, 60,000, 65,000, or 70,000 daltons, and more
preferably about 20,000 daltons is employed. In certain
embodiments, however, higher or lower molecular weights can be
preferred. Additionally, a casting solution or dispersion of
cellulose acetate butyrate at a weight percent of about 15% to
about 25%, preferably from about 15%, 16%, 17%, 18%, 19% to about
20%, 21%, 22%, 23%, 24% or 25%, and more preferably about 18% is
preferred. Preferably, the casting solution includes a solvent or
solvent system, for example an acetone:ethanol solvent system.
Higher or lower concentrations can be preferred in certain
embodiments. A plurality of layers of cellulose acetate butyrate
can be advantageously combined to form the interference domain in
some embodiments, for example, three layers can be employed. It can
be desirable to employ a mixture of cellulose acetate butyrate
components with different molecular weights in a single solution,
or to deposit multiple layers of cellulose acetate butyrate from
different solutions comprising cellulose acetate butyrate of
different molecular weights, different concentrations, and/or
different chemistries (e.g., functional groups). It can also be
desirable to include additional substances in the casting solutions
or dispersions, e.g., functionalizing agents, crosslinking agents,
other polymeric substances, substances capable of modifying the
hydrophilicity/hydrophobicity of the resulting layer, and the
like.
In one alternative embodiment, the interference domain is formed
from cellulose acetate. Cellulose acetate with a molecular weight
of about 30,000 daltons or less to about 100,000 daltons or more,
preferably from about 35,000, 40,000, or 45,000 daltons to about
55,000, 60,000, 65,000, 70,000, 75,000, 80,000, 85,000, 90,000, or
95,000 daltons, and more preferably about 50,000 daltons is
preferred. Additionally, a casting solution or dispersion of
cellulose acetate at a weight percent of about 3% to about 10%,
preferably from about 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, or 6.5%
to about 7.5%, 8.0%, 8.5%, 9.0%, or 9.5%, and more preferably about
8% is preferred. In certain embodiments, however, higher or lower
molecular weights and/or cellulose acetate weight percentages can
be preferred. It can be desirable to employ a mixture of cellulose
acetates with molecular weights in a single solution, or to deposit
multiple layers of cellulose acetate from different solutions
comprising cellulose acetates of different molecular weights,
different concentrations, or different chemistries (e.g.,
functional groups). It can also be desirable to include additional
substances in the casting solutions or dispersions such as
described in more detail above.
Layer(s) prepared from combinations of cellulose acetate and
cellulose acetate butyrate, or combinations of layer(s) of
cellulose acetate and layer(s) of cellulose acetate butyrate can
also be employed to form the interference domain.
In some alternative embodiments, additional polymers, such as
Nafion.RTM., can be used in combination with cellulosic derivatives
to provide equivalent and/or enhanced function of the interference
domain. As one example, a 5 wt % Nafion.RTM. casting solution or
dispersion can be used in combination with a 8 wt % cellulose
acetate casting solution or dispersion, e.g., by dip coating at
least one layer of cellulose acetate and subsequently dip coating
at least one layer Nafion.RTM. onto a needle-type sensor such as
described with reference to the preferred embodiments. Any number
of coatings or layers formed in any order may be suitable for
forming the interference domain of the preferred embodiments.
In some alternative embodiments, more than one cellulosic
derivative can be used to form the interference domain of the
preferred embodiments. In general, the formation of the
interference domain on a surface utilizes a solvent or solvent
system in order to solvate the cellulosic derivative (or other
polymer) prior to film formation thereon. In preferred embodiments,
acetone and ethanol are used as solvents for cellulose acetate;
however one skilled in the art appreciates the numerous solvents
that are suitable for use with cellulosic derivatives (and other
polymers). Additionally, one skilled in the art appreciates that
the preferred relative amounts of solvent can be dependent upon the
cellulosic derivative (or other polymer) used, its molecular
weight, its method of deposition, its desired thickness, and the
like. However, a percent solute of from about 1% to about 25% is
preferably used to form the interference domain solution so as to
yield an interference domain having the desired properties. The
cellulosic derivative (or other polymer) used, its molecular
weight, method of deposition, and desired thickness can be
adjusted, depending upon one or more other of the parameters, and
can be varied accordingly as is appreciated by one skilled in the
art.
In some alternative embodiments, other polymer types that can be
utilized as a base material for the interference domain including
polyurethanes, polymers having pendant ionic groups, and polymers
having controlled pore size, for example. In one such alternative
embodiment, the interference domain includes a thin, hydrophobic
membrane that is non-swellable and restricts diffusion of low
molecular weight species. The interference domain is permeable to
relatively low molecular weight substances, such as hydrogen
peroxide, but restricts the passage of higher molecular weight
substances, including glucose and ascorbic acid. Other systems and
methods for reducing or eliminating interference species that can
be applied to the membrane system of the preferred embodiments are
described in U.S. Publication No. US-2005-0115832-A1, U.S.
Publication No. US-2005-0176136-A1, U.S. Publication No.
US-2005-0161346-A1, and U.S. Publication No. US-2005-0143635-A1. In
some alternative embodiments, a distinct interference domain is not
included.
In preferred embodiments, the interference domain is deposited
directly onto the electroactive surfaces of the sensor for a domain
thickness of from about 0.05 micron or less to about 20 microns or
more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,
0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5
microns, and more preferably still from about 1, 1.5 or 2 microns
to about 2.5 or 3 microns. Thicker membranes can also be desirable
in certain embodiments, but thinner membranes are generally
preferred because they have a lower impact on the rate of diffusion
of hydrogen peroxide from the enzyme membrane to the
electrodes.
In general, the membrane systems of the preferred embodiments can
be formed and/or deposited on the exposed electroactive surfaces
(e.g., one or more of the working and reference electrodes) using
known thin film techniques (for example, casting, spray coating,
drawing down, electro-depositing, dip coating, and the like),
however casting or other known application techniques can also be
utilized. Preferably, the interference domain is deposited by vapor
deposition, spray coating, or dip coating. In one exemplary
embodiment of a needle-type (transcutaneous) sensor such as
described herein, the interference domain is formed by dip coating
the sensor into an interference domain solution using an insertion
rate of from about 20 inches/min to about 60 inches/min, preferably
40 inches/min, a dwell time of from about 0 minute to about 5
seconds, preferably 0 seconds, and a withdrawal rate of from about
20 inches/minute to about 60 inches/minute, preferably about 40
inches/minute, and curing (drying) the domain from about 1 minute
to about 30 minutes, preferably from about 3 minutes to about 15
minutes (and can be accomplished at room temperature or under
vacuum (e.g., 20 to 30 mmHg)). In one exemplary embodiment
including cellulose acetate butyrate interference domain, a
3-minute cure (i.e., dry) time is preferred between each layer
applied. In another exemplary embodiment employing a cellulose
acetate interference domain, a 15 minute cure (i.e., dry) time is
preferred between each layer applied.
The dip process can be repeated at least one time and up to 10
times or more. The preferred number of repeated dip processes
depends upon the cellulosic derivative(s) used, their
concentration, conditions during deposition (e.g., dipping) and the
desired thickness (e.g., sufficient thickness to provide functional
blocking of (or resistance to) certain interferents), and the like.
In some embodiments, 1 to 3 microns may be preferred for the
interference domain thickness; however, values outside of these can
be acceptable or even desirable in certain embodiments, for
example, depending upon viscosity and surface tension, as is
appreciated by one skilled in the art. In one exemplary embodiment,
an interference domain is formed from three layers of cellulose
acetate butyrate. In another exemplary embodiment, an interference
domain is formed from 10 layers of cellulose acetate. In another
exemplary embodiment, an interference domain is formed of one
relatively thicker layer of cellulose acetate butyrate. In yet
another exemplary embodiment, an interference domain is formed of
four relatively thinner layers of cellulose acetate butyrate. In
alternative embodiments, the interference domain can be formed
using any known method and combination of cellulose acetate and
cellulose acetate butyrate, as will be appreciated by one skilled
in the art.
In some embodiments, the electroactive surface can be cleaned prior
to application of the interference domain. In some embodiments, the
interference domain of the preferred embodiments can be useful as a
bioprotective or biocompatible domain, namely, a domain that
interfaces with host tissue when implanted in an animal (e.g., a
human) due to its stability and biocompatibility.
Enzyme Domain
In preferred embodiments, the membrane system further includes an
enzyme domain 28 disposed more distally from the electroactive
surfaces than the interference domain; however other configurations
can be desirable (FIGS. 2A-2B). In the preferred embodiments, the
enzyme domain provides an enzyme to catalyze the reaction of the
analyte and its co-reactant, as described in more detail below. In
the preferred embodiments of a glucose sensor, the enzyme domain
includes glucose oxidase; however other oxidases, for example,
galactose oxidase or uricase oxidase, can also be used.
For an enzyme-based electrochemical glucose sensor to perform well,
the sensor's response is preferably limited by neither enzyme
activity nor co-reactant concentration. Because enzymes, including
glucose oxidase (GOx), are subject to deactivation as a function of
time even in ambient conditions, this behavior is compensated for
in forming the enzyme domain. Preferably, the enzyme domain is
constructed of aqueous dispersions of colloidal polyurethane
polymers including the enzyme. However, in alternative embodiments
the enzyme domain is constructed from an oxygen enhancing material,
for example, silicone, or fluorocarbon, in order to provide a
supply of excess oxygen during transient ischemia. Preferably, the
enzyme is immobilized within the domain. See, e.g., U.S.
Publication No. US-2005-0054909-A1.
In preferred embodiments, the enzyme domain is deposited onto the
interference domain for a domain thickness of from about 0.05
micron or less to about 20 microns or more, more preferably from
about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,
1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more
preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,
4.5, or 5 microns. However in some embodiments, the enzyme domain
can be deposited directly onto the electroactive surfaces.
Preferably, the enzyme domain is deposited by spray or dip coating.
In one embodiment of needle-type (transcutaneous) sensor such as
described herein, the enzyme domain is formed by dip coating the
interference domain coated sensor into an enzyme domain solution
and curing the domain for from about 15 to about 30 minutes at a
temperature of from about 40.degree. C. to about 55.degree. C. (and
can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In
embodiments wherein dip coating is used to deposit the enzyme
domain at room temperature, a preferred insertion rate of from
about 0.25 inch per minute to about 3 inches per minute, with a
preferred dwell time of from about 0.5 minutes to about 2 minutes,
and a preferred withdrawal rate of from about 0.25 inch per minute
to about 2 inches per minute provides a functional coating.
However, values outside of those set forth above can be acceptable
or even desirable in certain embodiments, for example, depending
upon viscosity and surface tension, as is appreciated by one
skilled in the art. In one embodiment, the enzyme domain is formed
by dip coating two times (namely, forming two layers) in an enzyme
domain solution and curing at 50.degree. C. under vacuum for 20
minutes. However, in some embodiments, the enzyme domain can be
formed by dip coating and/or spray coating one or more layers at a
predetermined concentration of the coating solution, insertion
rate, dwell time, withdrawal rate, and/or desired thickness.
Resistance Domain
In preferred embodiments, the membrane system includes a resistance
domain 30 disposed more distal from the electroactive surfaces than
the enzyme domain (FIGS. 2A-2B). Although the following description
is directed to a resistance domain for a glucose sensor, the
resistance domain can be modified for other analytes and
co-reactants as well.
There exists a molar excess of glucose relative to the amount of
oxygen in blood; that is, for every free oxygen molecule in
extracellular fluid, there are typically more than 100 glucose
molecules present (see Updike et al., Diabetes Care
5:207-21(1982)). However, an immobilized enzyme-based glucose
sensor employing oxygen as co-reactant is preferably supplied with
oxygen in non-rate-limiting excess in order for the sensor to
respond linearly to changes in glucose concentration, while not
responding to changes in oxygen concentration. Specifically, when a
glucose-monitoring reaction is oxygen limited, linearity is not
achieved above minimal concentrations of glucose. Without a
semipermeable membrane situated over the enzyme domain to control
the flux of glucose and oxygen, a linear response to glucose levels
can be obtained only for glucose concentrations of up to about 40
mg/dL. However, in a clinical setting, a linear response to glucose
levels is desirable up to at least about 400 mg/dL.
The resistance domain includes a semipermeable membrane that
controls the flux of oxygen and glucose to the underlying enzyme
domain, preferably rendering oxygen in a non-rate-limiting excess.
As a result, the upper limit of linearity of glucose measurement is
extended to a much higher value than that which is achieved without
the resistance domain. In one embodiment, the resistance domain
exhibits an oxygen to glucose permeability ratio of from about 50:1
or less to about 400:1 or more, preferably about 200:1. As a
result, one-dimensional reactant diffusion is adequate to provide
excess oxygen at all reasonable glucose and oxygen concentrations
found in the subcutaneous matrix (See Rhodes et al., Anal. Chem.,
66:1520-1529 (1994)).
In alternative embodiments, a lower ratio of oxygen-to-glucose can
be sufficient to provide excess oxygen by using a high oxygen
solubility domain (for example, a silicone or fluorocarbon-based
material or domain) to enhance the supply/transport of oxygen to
the enzyme domain. If more oxygen is supplied to the enzyme, then
more glucose can also be supplied to the enzyme without creating an
oxygen rate-limiting excess. In alternative embodiments, the
resistance domain is formed from a silicone composition, such as is
described in U.S. Publication No. US-2005-0090607-A1.
In a preferred embodiment, the resistance domain includes a
polyurethane membrane with both hydrophilic and hydrophobic regions
to control the diffusion of glucose and oxygen to an analyte
sensor, the membrane being fabricated easily and reproducibly from
commercially available materials. A suitable hydrophobic polymer
component is a polyurethane, or polyetherurethaneurea. Polyurethane
is a polymer produced by the condensation reaction of a
diisocyanate and a difunctional hydroxyl-containing material. A
polyurethaneurea is a polymer produced by the condensation reaction
of a diisocyanate and a difunctional amine-containing material.
Preferred diisocyanates include aliphatic diisocyanates containing
from about 4 to about 8 methylene units. Diisocyanates containing
cycloaliphatic moieties can also be useful in the preparation of
the polymer and copolymer components of the membranes of preferred
embodiments. The material that forms the basis of the hydrophobic
matrix of the resistance domain can be any of those known in the
art as appropriate for use as membranes in sensor devices and as
having sufficient permeability to allow relevant compounds to pass
through it, for example, to allow an oxygen molecule to pass
through the membrane from the sample under examination in order to
reach the active enzyme or electrochemical electrodes. Examples of
materials which can be used to make non-polyurethane type membranes
include vinyl polymers, polyethers, polyesters, polyamides,
inorganic polymers such as polysiloxanes and polycarbosiloxanes,
natural polymers such as cellulosic and protein based materials,
and mixtures or combinations thereof.
In a preferred embodiment, the hydrophilic polymer component is
polyethylene oxide. For example, one useful hydrophobic-hydrophilic
copolymer component is a polyurethane polymer that includes about
20% hydrophilic polyethylene oxide. The polyethylene oxide portions
of the copolymer are thermodynamically driven to separate from the
hydrophobic portions of the copolymer and the hydrophobic polymer
component. The 20% polyethylene oxide-based soft segment portion of
the copolymer used to form the final blend affects the water
pick-up and subsequent glucose permeability of the membrane.
In some embodiments, the resistance domain is formed from a
silicone polymer modified to allow analyte (e.g., glucose)
transport.
In some embodiments, the resistance domain is formed from a
silicone polymer/hydrophobic-hydrophilic polymer blend. In one
embodiment, The hydrophobic-hydrophilic polymer for use in the
blend may be any suitable hydrophobic-hydrophilic polymer,
including but not limited to components such as
polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,
polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene
glycol or polypropylene oxide, and copolymers thereof, including,
for example, di-block, tri-block, alternating, random, comb, star,
dendritic, and graft copolymers (block copolymers are discussed in
U.S. Pat. Nos. 4,803,243 and 4,686,044, which are incorporated
herein by reference). In one embodiment, the
hydrophobic-hydrophilic polymer is a copolymer of poly(ethylene
oxide) (PEO) and poly(propylene oxide) (PPO). Suitable such
polymers include, but are not limited to, PEO-PPO diblock
copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock
copolymers, alternating block copolymers of PEO-PPO, random
copolymers of ethylene oxide and propylene oxide, and blends
thereof. In some embodiments, the copolymers may be optionally
substituted with hydroxy substituents. Commercially available
examples of PEO and PPO copolymers include the PLURONIC.RTM. brand
of polymers available from BASF.RTM.. In one embodiment,
PLURONIC.RTM. F-127 is used. Other PLURONIC.RTM. polymers include
PPO-PEO-PPO triblock copolymers (e.g., PLURONIC.RTM. R products).
Other suitable commercial polymers include, but are not limited to,
SYNPERONICS.RTM. products available from UNIQEMA.RTM..
In preferred embodiments, the resistance domain is deposited onto
the enzyme domain to yield a domain thickness of from about 0.05
microns or less to about 20 microns or more, more preferably from
about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1,
1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more
preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,
4.5, or 5 microns. Preferably, the resistance domain is deposited
onto the enzyme domain by vapor deposition, spray coating, or dip
coating. In one preferred embodiment, spray coating is the
preferred deposition technique. The spraying process atomizes and
mists the solution, and therefore most or all of the solvent is
evaporated prior to the coating material settling on the underlying
domain, thereby minimizing contact of the solvent with the
enzyme.
In a preferred embodiment, the resistance domain is deposited on
the enzyme domain by spray coating a solution of from about 1 wt. %
to about 5 wt. % polymer and from about 95 wt. % to about 99 wt. %
solvent. In spraying a solution of resistance domain material,
including a solvent, onto the enzyme domain, it is desirable to
mitigate or substantially reduce any contact with enzyme of any
solvent in the spray solution that can deactivate the underlying
enzyme of the enzyme domain. Tetrahydrofuran (THF) is one solvent
that minimally or negligibly affects the enzyme of the enzyme
domain upon spraying. Other solvents can also be suitable for use,
as is appreciated by one skilled in the art.
Preferably, each exemplary sensor design (e.g., FIGS. 1A, 2A, and
7A through 9B) includes electronic connections, for example, one or
more electrical contacts configured to provide secure electrical
contact between the sensor and associated electronics. In some
embodiments, the electrodes and membrane systems of the preferred
embodiments are coaxially formed, namely, the electrodes and/or
membrane system all share the same central axis. While not wishing
to be bound by theory, it is believed that a coaxial design of the
sensor enables a symmetrical design without a preferred bend
radius. Namely, in contrast to prior art sensors comprising a
substantially planar configuration that can suffer from regular
bending about the plane of the sensor, the coaxial design of the
preferred embodiments do not have a preferred bend radius and
therefore are not subject to regular bending about a particular
plane (which can cause fatigue failures and the like). However,
non-coaxial sensors can be implemented with the sensor system of
the preferred embodiments.
In addition to the above-described advantages, the coaxial sensor
design of the preferred embodiments enables the diameter of the
connecting end of the sensor (proximal portion) to be substantially
the same as that of the sensing end (distal portion) such that a
needle is able to insert the sensor into the host and subsequently
slide back over the sensor and release the sensor from the needle,
without slots or other complex multi-component designs, as
described in detail in U.S. Publication No. US-2006-0063142-A1 and
U.S. application Ser. No. 11/360,250 filed Feb. 22, 2006 and
entitled "ANALYTE SENSOR," which are incorporated in their entirety
herein by reference.
Exemplary Continuous Sensor Configurations
In some embodiments, the sensor is an enzyme-based electrochemical
sensor, wherein the glucose-measuring working electrode 16 (e.g.,
FIGS. 1A-1B) measures the hydrogen peroxide produced by the enzyme
catalyzed reaction of glucose being detected and creates a
measurable electronic current (for example, detection of glucose
utilizing glucose oxidase produces hydrogen peroxide
(H.sub.2O.sub.2) as a by product, H.sub.2O.sub.2 reacts with the
surface of the working electrode producing two protons (2H.sup.+),
two electrons (2e.sup.-) and one molecule of oxygen (O.sub.2) which
produces the electronic current being detected, see FIG. 10), such
as described in more detail elsewhere herein and as is appreciated
by one skilled in the art. Preferably, one or more potentiostat is
employed to monitor the electrochemical reaction at the
electroactive surface of the working electrode(s). The potentiostat
applies a constant potential to the working electrode and its
associated reference electrode to determine the current produced at
the working electrode. The current that is produced at the working
electrode (and flows through the circuitry to the counter
electrode) is substantially proportional to the amount of
H.sub.2O.sub.2 that diffuses to the working electrodes. The output
signal is typically a raw data stream that is used to provide a
useful value of the measured analyte concentration in a host to the
patient or doctor, for example.
Some alternative analyte sensors that can benefit from the systems
and methods of the preferred embodiments include U.S. Pat. No.
5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 to Vachon et al.,
U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No. 6,565,509 to
Say et al., U.S. Pat. No. 6,514,718 to Heller, U.S. Pat. No.
6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 to
Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al.,
and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No.
6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et
al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No.
6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 to
Mastrototaro et al, for example. All of the above patents are
incorporated in their entirety herein by reference and are not
inclusive of all applicable analyte sensors; in general, it should
be understood that the disclosed embodiments are applicable to a
variety of analyte sensor configurations.
Although some exemplary glucose sensor configurations are described
in detail below, it should be understood that the systems and
methods described herein can be applied to any device capable of
continually or continuously detecting a concentration of analyte of
interest and providing an output signal that represents the
concentration of that analyte, for example oxygen, lactose,
hormones, cholesterol, medicaments, viruses, or the like.
FIG. 1A is a perspective view of an analyte sensor, including an
implantable body with a sensing region including a membrane system
disposed thereon. In the illustrated embodiment, the analyte sensor
10a includes a body 12 and a sensing region 14 including membrane
and electrode systems configured to measure the analyte. In this
embodiment, the sensor 10a is preferably wholly implanted into the
subcutaneous tissue of a host, such as described in U.S.
Publication No. US-2006-0015020-A1; U.S. Publication No.
US-2005-0245799-A1; U.S. Publication No. US-2005-0192557-A1; U.S.
Publication No. US-2004-0199059-A1; U.S. Publication No.
US-2005-0027463-A1; and U.S. Pat. No. 6,001,067 issued Dec. 14,
1999 and entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE
LEVELS," each of which are incorporated herein by reference in
their entirety.
The body 12 of the sensor 10a can be formed from a variety of
materials, including metals, ceramics, plastics, or composites
thereof. In one embodiment, the sensor is formed from thermoset
molded around the sensor electronics. U.S. Publication No.
US-2004-0199059-A1 discloses suitable configurations for the body,
and is incorporated by reference in its entirety.
In some embodiments, the sensing region 14 includes a
glucose-measuring working electrode 16, an optional auxiliary
working electrode 18, a reference electrode 20, and a counter
electrode 24. Generally, the sensing region 14 includes means to
measure two different signals, 1) a first signal associated with
glucose and non-glucose related electroactive compounds having a
first oxidation potential, wherein the first signal is measured at
the glucose-measuring working electrode disposed beneath an active
enzymatic portion of a membrane system, and 2) a second signal
associated with the baseline and/or sensitivity of the glucose
sensor. In some embodiments, wherein the second signal measures
sensitivity, the signal is associated with at least one non-glucose
constant data point, for example, wherein the auxiliary working
electrode 18 is configured to measure oxygen. In some embodiments,
wherein the second signal measures baseline, the signal is
associated with non-glucose related electroactive compounds having
the first oxidation potential, wherein the second signal is
measured at an auxiliary working electrode 18 and is disposed
beneath a non-enzymatic portion of the membrane system, such as
described in more detail elsewhere herein.
Preferably, a membrane system (see FIG. 2A) is deposited over the
electroactive surfaces of the sensor 10a and includes a plurality
of domains or layers, such as described in more detail below, with
reference to FIGS. 2A and 2B. In general, the membrane system may
be disposed over (deposited on) the electroactive surfaces using
methods appreciated by one skilled in the art. See U.S. Publication
No. US-2006-0015020-A1.
The sensing region 14 comprises electroactive surfaces, which are
in contact with an electrolyte phase (not shown), which is a
free-flowing fluid phase disposed between the membrane system 22
and the electroactive surfaces. In this embodiment, the counter
electrode is provided to balance the current generated by the
species being measured at the working electrode. In the case of
glucose oxidase based analyte sensors, the species being measured
at the working electrode is H.sub.2O.sub.2. Glucose oxidase
catalyzes the conversion of oxygen and glucose to hydrogen peroxide
and gluconate according to the following reaction:
Glucose+O.sub.2.fwdarw.Gluconate+H.sub.2O.sub.2
The change in H.sub.2O.sub.2 can be monitored to determine glucose
concentration because for each glucose molecule metabolized, there
is a proportional change in the product H.sub.2O.sub.2 (see FIG.
10). Oxidation of H.sub.2O.sub.2 by the working electrode is
balanced by reduction of ambient oxygen, enzyme generated
H.sub.2O.sub.2, or other reducible species at the counter
electrode. The H.sub.2O.sub.2 produced from the glucose oxidase
reaction further reacts at the surface of the working electrode and
produces two protons (2H.sup.+), two electrons (2e.sup.-), and one
oxygen molecule (O.sub.2). Preferably, one or more potentiostats
are employed to monitor the electrochemical reaction at the
electroactive surface of the working electrode(s). The potentiostat
applies a constant potential to the working electrode and its
associated reference electrode to determine the current produced at
the working electrode. The current that is produced at the working
electrode (and flows through the circuitry to the counter
electrode) is substantially proportional to the amount of
H.sub.2O.sub.2 that diffuses to the working electrodes. The output
signal is typically a raw data stream that is used to provide a
useful value of the measured analyte concentration in a host to the
patient or doctor, for example.
FIG. 1B is a schematic view of an alternative exemplary embodiment
of a continuous analyte sensor 10b, also referred to as an
in-dwelling or transcutaneous analyte sensor in some circumstances,
particularly illustrating the in vivo portion of the sensor. In
this embodiment, the in vivo portion of the sensor 10b is the
portion adapted for insertion under the host's skin, in a host's
blood stream, or other biological sample, while an ex vivo portion
of the sensor (not shown) is the portion that remains above the
host's skin after sensor insertion and operably connects to an
electronics unit. In the illustrated embodiment, the analyte sensor
10b is coaxial and includes three electrodes: a glucose-measuring
working electrode 16, an optional auxiliary working electrode 18,
and at least one additional electrode 20, which may function as a
counter and/or reference electrode, hereinafter referred to as the
reference electrode 20. Generally, the sensor 10b may include the
ability to measure two different signals, 1) a first signal
associated with glucose and non-glucose related electroactive
compounds having a first oxidation potential, wherein the first
signal is measured at the glucose-measuring working electrode
disposed beneath an active enzymatic portion of a membrane system,
and 2) a second signal associated with the baseline and/or
sensitivity of the glucose sensor, such as described in more detail
above with reference to FIG. 1A.
One skilled in the art appreciates that the analyte sensor of FIG.
1B can have a variety of configurations. In one exemplary
embodiment, the sensor is generally configured of a first working
electrode, a second working electrode, and a reference electrode.
In one exemplary configuration, the first working electrode 16 is a
central metal wire or plated non-conductive rod/filament/fiber and
the second working and reference electrodes (20 and 18,
respectively OR 18 and 20, respectively) are coiled around the
first working electrode 16. In another exemplary configuration, the
first working electrode is a central wire, as depicted in FIG. 1B,
the second working electrode is coiled around the first working
electrode, and the reference electrode is disposed remotely from
the sensor, as described herein. In another exemplary
configuration, the first and second working electrodes (20 and 18)
are coiled around a supporting rod 16 of insulating material. The
reference electrode (not shown) can be disposed remotely from the
sensor, as described herein, or disposed on the non-conductive
supporting rod 16. In still another exemplary configuration, the
first and second working electrodes (20 and 18) are coiled around a
reference electrode 16 (not to scale).
Preferably, each electrode is formed from a fine wire, with a
diameter in the range of 0.001 to 0.010 inches, for example, and
may be formed from plated wire or bulk material, however the
electrodes may be deposited on a substrate or other known
configurations as is appreciated by one skilled in the art.
In one embodiment, the glucose-measuring working electrode 16
comprises a wire formed from a conductive material, such as
platinum, palladium, graphite, gold, carbon, conductive polymer, or
the like. Alternatively, the glucose-measuring working electrode 16
can be formed of a non-conductive fiber or rod that is plated with
a conductive material. The glucose-measuring working electrode 16
is configured and arranged to measure the concentration of glucose.
The glucose-measuring working electrode 16 is covered with an
insulating material, for example a non-conductive polymer.
Dip-coating, spray-coating, or other coating or deposition
techniques can be used to deposit the insulating material on the
working electrode, for example. In one preferred embodiment, the
insulating material comprises Parylene, which can be an
advantageous conformal coating for its strength, lubricity, and
electrical insulation properties, however, a variety of other
insulating materials can be used, for example, fluorinated
polymers, polyethyleneterephthalate, polyurethane, polyimide, or
the like.
In this embodiment, the auxiliary working electrode 18 comprises a
wire formed from a conductive material, such as described with
reference to the glucose-measuring working electrode 16 above.
Preferably, the reference electrode 20, which may function as a
reference electrode alone, or as a dual reference and counter
electrode, is formed from silver, Silver/Silver chloride, or the
like.
Preferably, the electrodes are juxtapositioned and/or twisted with
or around each other; however other configurations are also
possible. In one example, the auxiliary working electrode 18 and
reference electrode 20 may be helically wound around the
glucose-measuring working electrode 16 as illustrated in FIG. 1B.
Alternatively, the auxiliary working electrode 18 and reference
electrode 20 may be formed as a double helix around a length of the
glucose-measuring working electrode 16. In some embodiments, the
working electrode, auxiliary working electrode and reference
electrodes may be formed as a triple helix. The assembly of wires
may then be optionally coated together with an insulating material,
similar to that described above, in order to provide an insulating
attachment. Some portion of the coated assembly structure is then
stripped, for example using an excimer laser, chemical etching, or
the like, to expose the necessary electroactive surfaces. In some
alternative embodiments, additional electrodes may be included
within the assembly, for example, a three-electrode system
(including separate reference and counter electrodes) as is
appreciated by one skilled in the art.
FIGS. 2A and 2B are schematic views membrane systems in some
embodiments that may be disposed over the electroactive surfaces of
an analyte sensors of FIGS. 1A and 1B, respectively, wherein the
membrane system includes one or more of the following domains: a
resistance domain 30, an enzyme domain 28, an optional interference
domain 26, and an electrolyte domain 24, such as described in more
detail below. However, it is understood that the membrane system 22
can be modified for use in other sensors, by including only one or
more of the domains, additional domains not recited above, or for
other sensor configurations. For example, the interference domain
can be removed when other methods for removing interferants are
utilized, such as an auxiliary electrode for measuring and
subtracting out signal due to interferants. As another example, an
"oxygen antenna domain" composed of a material that has higher
oxygen solubility than aqueous media so that it concentrates oxygen
from the biological fluid surrounding the biointerface membrane can
be added. The oxygen antenna domain can then act as an oxygen
source during times of minimal oxygen availability and has the
capacity to provide on demand a higher rate of oxygen delivery to
facilitate oxygen transport to the membrane. This enhances function
in the enzyme reaction domain and at the counter electrode surface
when glucose conversion to hydrogen peroxide in the enzyme domain
consumes oxygen from the surrounding domains. Thus, this ability of
the oxygen antenna domain to apply a higher flux of oxygen to
critical domains when needed improves overall sensor function.
In some embodiments, the membrane system generally provides one or
more of the following functions: 1) protection of the exposed
electrode surface from the biological environment, 2) diffusion
resistance (limitation) of the analyte, 3) a catalyst for enabling
an enzymatic reaction, 4) optionally limitation or blocking of
interfering species, and 5) hydrophilicity at the electrochemically
reactive surfaces of the sensor interface, such as described in
U.S. Publication No. US-2005-0245799-A1. In some embodiments, the
membrane system additionally includes a cell disruptive domain, a
cell impermeable domain, and/or an oxygen domain (not shown), such
as described in more detail in U.S. Publication No.
US-2005-0245799-A1. However, it is understood that a membrane
system modified for other sensors, for example, by including fewer
or additional domains is within the scope of the preferred
embodiments.
One aspect of the preferred embodiments provides for a sensor (for
transcutaneous, wholly implantable, or intravascular short-term or
long-term use) having integrally formed parts, such as but not
limited to a plurality of electrodes, a membrane system and an
enzyme. For example, the parts may be coaxial, juxtapositioned,
helical, bundled and/or twisted, plated and/or deposited thereon,
extruded, molded, held together by another component, and the like.
In another example, the components of the electrode system are
integrally formed, (e.g., without additional support, such as a
supporting substrate), such that substantially all parts of the
system provide essential functions of the sensor (e.g., the sensing
mechanism or "in vivo" portion). In a further example, a first
electrode can be integrally formed directly on a second electrode
(e.g., electrically isolated by an insulator), such as by vapor
deposition of a conductive electrode material, screen printing a
conductive electrode ink or twisting two electrode wires together
in a coiled structure.
Some embodiments provide an analyte sensor that is configured for
insertion into a host and for measuring an analyte in the host,
wherein the sensor includes a first working electrode disposed
beneath an active enzymatic portion of a membrane (e.g., membrane
system) on the sensor and a second working electrode disposed
beneath an inactive- or non-enzymatic portion of the membrane on
the sensor. In these embodiments, the first and second working
electrodes integrally form at least a portion of the sensor.
Exemplary Sensor Configurations
FIG. 1B is a schematic view of a sensor in one embodiment. In some
preferred embodiments, the sensor is configured to be integrally
formed and coaxial. In this exemplary embodiment, one or more
electrodes are helically wound around a central core, all of which
share axis A-A. The central core 16 can be an electrode (e.g., a
wire or metal-plated insulator) or a support made of insulating
material. The coiled electrodes 18, 20 are made of conductive
material (e.g., plated wire, metal-plated polymer filaments, bulk
metal wires, etc.) that is helically wound or twisted about the
core 16. Generally, at least the working electrodes are coated with
an insulator I of non-conductive or dielectric material.
One skilled in the art will recognize that various electrode
combinations are possible. For example, in one embodiment, the core
16 is a first working electrode and can be substantially straight.
One of the coiled electrodes (18 or 20) is a second working
electrode and the remaining coiled electrode is a reference or
counter electrode. In a further embodiment, the reference electrode
can be disposed remotely from the sensor, such as on the host's
skin or on the exterior of the sensor, for example. Although this
exemplary embodiment illustrates an integrally formed coaxial
sensor, one skilled in the art appreciates a variety of alternative
configurations. In one exemplary embodiment, the arrangement of
electrodes is reversed, wherein the first working electrode is
helically wound around the second working electrode core 16. In
another exemplary embodiment, the reference electrode can form the
central core 16 with the first and second working electrodes coiled
there around. In some exemplary embodiments, the sensor can have
additional working, reference and/or counter electrodes, depending
upon the sensor's purpose. Generally, one or more of the electrode
wires are coated with an insulating material, to prevent direct
contact between the electrodes. Generally, a portion of the
insulating material can be removed (e.g., etched, scraped or
grit-blasted away) to expose an electroactive surface of the
electrode. An enzyme solution can be applied to the exposed
electroactive surface, as described herein.
The electrodes each have first and second ends. The electrodes can
be of any geometric solid shape, such as but not limited to a
cylinder having a circular or oval cross-section, a rectangle
(e.g., extruded rectangle), a triangle (e.g., extruded triangle),
an X-cross section, a Y-cross section, flower petal-cross sections,
star-cross sections, melt-blown fibers loaded with conductive
material (e.g., conductive polymers) and the like. The first ends
(e.g., an in vivo portion, "front end") of the electrodes are
configured for insertion in the host and the second ends (e.g., an
ex vivo portion, "back end") are configured for electrical
connection to sensor electronics. In some embodiments, the sensor
includes sensor electronics that collect data from the sensor and
provide the data to the host in various ways. Sensor electronics
are discussed in detail elsewhere herein.
FIGS. 7A1 and 7A2 are schematics of an analyte sensor in another
embodiment. FIG. 7A1 is a side view and FIG. 7A2 is a side-cutaway
view. In some preferred embodiments, the sensor is configured to be
integrally formed and coaxial, with an optional stepped end. In
this exemplary embodiment, the sensor includes a plurality of
electrodes E1, E2, E3 to En, wherein n equals any number of
electrode layers. Layers of insulating material I (e.g.,
non-conductive material) separate the electrode layers. All of the
electrode and insulating material layers share axis A-A. The layers
can be applied by any technique known in the art, such as but not
limited to spraying, dipping, spraying, etc. For example, a bulk
metal wire electrode E1 can be dipped into a solution of insulating
polymer that is vulcanized to form a layer of non-conductive,
electrically insulating material I. A second electrode E2 can be
plated (e.g., by electroplating or other plating technique used in
the art) on the first insulating layer, followed by application of
a second insulating layer I applied in the same manner as the first
layer. Additional electrode layers (e.g., E3 to En) and insulating
layers can be added to the construct, to create the desired number
of electrodes and insulating layers. As an example, multiple
sensors can be formed from a long wire (with insulating and
electrode layers applied) that can be cut to yield a plurality of
sensors of the desired length. After the sensor has been cut to
size, it can be polished or otherwise treated to prepare the
electrodes for use. In some embodiments, the various electrode
and/or insulator layers can be applied by dipping, spraying,
printing, vapor deposition, plating, spin coating or any other
method known in the art. Although this exemplary embodiment
illustrates an integrally formed coaxial sensor, one skilled in the
art appreciates a variety of alternative configurations. For
example, in some embodiments, the sensor can have two, three, four
or more electrodes separated by insulating material I. In another
embodiment, the analyte sensor has two or more electrodes, such as
but not limited to a first working electrode, an auxiliary working
electrode, a reference electrode and/or counter electrode. FIG. 7B
is a schematic view of an integrally formed, coaxial sensor in
another embodiment. In this exemplary embodiment, a coiled first
electrode E1 is manufactured from an electrically conductive tube
or cylinder, such as but not limited to a silver Hypotube. A
portion of the Hypotube is trimmed or carved into a helix or coil
702. A second electrode E2 that is sized to fit (e.g., with minimal
tolerance) within the first electrode E1 mates (e.g., slides into)
with the first electrode E1, to form the sensor. In general, the
surfaces of the electrodes are coated with an insulator, to prevent
direct contact between the electrodes. As described herein, portion
of the insulator can be stripped away to expose the electroactive
surfaces. Although this exemplary embodiment illustrates one
configuration of a coaxial, integrally formed sensor, one skilled
in the art appreciates a variety of alternative configurations. For
example, in some embodiments, the first electrode E1 is a reference
or auxiliary electrode, and the second electrode E2 is a working
electrode. However, the first electrode E1 can be a working
electrode and the second electrode E2 can be a reference or
auxiliary electrode. In some embodiments, additional electrodes are
applied to the construct (e.g., after E2 is inserted into E1). One
advantage of this configuration is that the silver Hypotube can be
cut to increase or decrease the flexibility of the sensor. For
example, the spiral cut can space the coils farther apart to
increase the sensor's flexibility. Another example of this
configuration is that it is easier to construct the sensor in this
manner, rather than winding one electrode around another (e.g., as
is done for the embodiment shown in FIG. 1B).
FIGS. 7C to 7E are schematics of three embodiments of bundled
analyte sensors. In these embodiments, of the sensors are
configured to be integrally formed sensors, wherein a plurality
(E1, E2, E3, to En) of electrodes are bundled, coiled or twisted to
form a portion of the sensor. In some embodiments, the electrodes
can be twisted or helically coiled to form a coaxial portion of the
sensor, which share the same axis. In one embodiment, the first and
second working electrodes are twisted or helically wound together,
to form at least a portion of the sensor (e.g., a glucose sensor).
For example, the electrodes can be twisted in a double helix. In
some embodiments, additional electrodes are provided and twisted,
coiled or wound with the first and second electrodes to form a
larger super helix, such as a triple helix, a quadruple helix, or
the like. For example, three wires (E1, E2, and E3) can be twisted
to form a triple helix. In still other embodiments, at least one
reference electrode can be disposed remotely from the working
electrodes, as described elsewhere herein. In some embodiments, the
tip of the sensor can be cut at an angle (90.degree. or other
angle) to expose the electrode tips to varying extents, as
described herein.
FIG. 7C is a schematic of an exemplary embodiment of a sensor
having three bundled electrodes E1, E2, and E3. In some preferred
embodiments of the sensor, two or all of the electrodes can be
identical. Alternatively, the electrodes can be non-identical. For
example, the sensor can have a glucose-sensing electrode, an
oxygen-sensing electrode and a reference electrode. Although this
exemplary embodiment illustrates a bundled sensor, one skilled in
the art appreciates a variety of alternative sensor configurations.
For example, only two electrodes can be used or more than three
electrodes can be used. In another example, holding one end of the
bundled wires in a clamp and twisting the other end of the wires,
to form a cable-like structure, can coil the electrodes together.
Such a coiled structure can hold the electrodes together without
additional structure (e.g., bound by a wire or coating). In another
example, non-coiled electrodes can be bundled and held together
with a wire or fiber coiled there around, or by applying a coating
of insulating material to the electrode bundle. In still another
example, the reference electrode can be disposed remotely from the
working electrodes, as described elsewhere herein.
FIG. 7D is a schematic view of a sensor in one embodiment. In some
preferred embodiments, the sensor is designed to be integrally
formed and bundled and/or coaxial. In this exemplary embodiment,
the sensor includes seven electrodes, wherein three electrodes of a
first type (e.g., 3.times.E1) and three electrodes of a second type
(e.g., 3.times.E2) are bundled around one electrode of a third type
(e.g., E3). Those skilled in the art appreciate a variety of
configurations possible with this embodiment. For example, the
different types of electrodes can be alternated or not alternated.
For example, in FIG. 7D, the two types of electrodes are
alternately disposed around E3. However, the two types of
electrodes can be grouped around the central structure. As
described herein, some or all of the electrodes can be coated with
a layer of insulating material, to prevent direct contact between
the electrodes. The electrodes can be coiled together, as in a
cable, or held together by a wire or fiber wrapping or a coating of
insulating material. The sensor can be cut, to expose the
electroactive surfaces of the electrodes, or portions of the
insulating material coating can be stripped away, as described
elsewhere herein. In another example, the sensor can include
additional (or fewer) electrodes. In one exemplary embodiment, the
E1 and E2 electrodes are bundled around a non-conductive core
(e.g., instead of electrode E3), such as an insulated fiber. In
another embodiment, different numbers of E1, E2, and E3 electrodes
can be used (e.g., two E1 electrodes, two E2 electrodes, and three
E3 electrodes). In another embodiment, additional electrode type
can be included in the sensor (e.g., an electrode of type E4, E5 or
E6, etc.). In still another exemplary embodiment, three
glucose-detecting electrodes (e.g., E1) and three reference
electrodes (e.g., E2) are bundled and (optionally) coiled around a
central auxiliary working electrode (e.g., E3).
FIG. 7E is a schematic of a sensor in another embodiment. In this
exemplary embodiment of an integrally formed sensor, two pairs of
electrodes (e.g., 2.times.E1 and 2.times.E2) are bundled around a
core of insulating material I. Fibers or strands of insulating
material I also separate the electrodes from each other. Although
this exemplary embodiment illustrates an integrally formed sensor,
one skilled in the art appreciates a variety of alternative
configurations. For example, the pair of E1 electrodes can be
working electrodes and the pair of E2 electrodes can be reference
and/or auxiliary electrodes. In one exemplary embodiment, the E1
electrodes are both glucose-detecting electrodes, a first E2
electrode is a reference electrode and a second E2 electrode is an
auxiliary electrode. In another exemplary embodiment, one E1
electrode includes active GOx and measures a glucose-related
signal; the other E1 electrode lacks active GOx and measures a
non-glucose-related signal, and the E2 electrodes are reference
electrodes. In yet another exemplary embodiment, one E1 electrode
detects glucose and the other E1 electrode detects urea, and both
E2 electrodes are reference electrodes. One skilled in the art of
electrochemical sensors will recognized that the size of the
various electrodes can be varied, depending upon their purpose and
the current and/or electrical potential used. Electrode size and
insulating material size/shape are not constrained by their
depiction of relative size in the Figures, which are schematic
schematics intended for only illustrative purposes.
FIG. 7F is a schematic view of a cross-section of an integrally
formed sensor in another embodiment. In some preferred embodiments,
the sensor is configured to be bifunctional. In this exemplary
embodiment, the sensor includes two working electrodes E1/E2
separated by either a reference electrode R or an insulating
material I. The electrodes E1, E2 and optionally the reference
electrode R are conductive and support the sensor's shape. In
addition, the reference electrode R (or the insulating material I)
can act as a diffusion barrier (D, described herein) between the
working electrodes E1, E2 and support the sensor's structure.
Although this exemplary embodiment illustrates one configuration of
an integrally formed sensor having bifunctional components, one
skilled in the art appreciates a variety of alternative
configurations. Namely, FIG. 7F is not to scale and the working
electrodes E1, E2 can be relatively larger or smaller in scale,
with regard to the reference electrode/insulator R/I separating
them. For example, in one embodiment, the working electrodes E1, E2
are separated by a reference electrode that has at least 6-times
the surface area of the working electrodes, combined. While the
working electrodes E1, E2 and reference electrode/insulator R/I are
shown and semi-circles and a rectangle, respectively, one skilled
in the art recognizes that these components can take on any
geometry know in the art, such as but not limited to rectangles,
cubes, cylinders, cones, and the like.
FIG. 7G is a schematic view of a sensor in yet another embodiment.
In some preferred embodiments, the sensor is configured to be
integrally formed with a diffusion barrier D, as described herein.
In this exemplary embodiment, the working electrodes E1, E2 (or one
working electrode and one counter electrode) are integrally formed
on a substantially larger reference electrode R or an insulator I
that substantially prevents diffusion of analyte or other species
from one working electrode to another working electrode (e.g., from
the enzymatic electrode (e.g., coated with active enzyme) to the
non-enzymatic electrode (e.g., no enzyme or inactive enzyme)).
Although this exemplary embodiment illustrates an integrally formed
sensor having a diffusion barrier, one skilled in the art
appreciates a variety of alternative configurations. For example,
in one embodiment, the reference electrode is designed to include
an exposed electroactive surface area that is at least equal to,
greater than, or more than about 2, 3, 4, 5, 6, 7, 8, 9, 10 or more
times greater than the surface area of the working electrodes
(e.g., combined). In other embodiments, the surface of the
reference electrode is about 6 (e.g., about 6 to 20) or more times
greater than the working electrodes. In some embodiments, each
working electrode detects a separate analyte (e.g., glucose,
oxygen, uric acid, nitrogen, pH, and the like). In other
embodiments, one of the working electrodes is a counter electrode.
In still another exemplary embodiment, an enzyme solution
containing active GOx is applied to the E1 electroactive surface,
while an enzyme solution containing inactive GOx (or no GOx at all)
is applied to the E2 electroactive surface. As described herein,
this configuration allows the measurement of two signals. Electrode
E1 measures both a signal related to glucose concentration and a
signal that is not related to glucose concentration. Electrode E2
measures a signal that is not related to glucose concentration. The
sensor electronics, as described herein, can use these data to
calculate glucose concentration without signal due to
non-glucose-related contributions.
FIG. 7H is a schematic view of a sensor in another embodiment. In
some preferred embodiments, the sensor is configured of a geometric
solid (e.g., cylindrical) reference electrode R having two or more
working electrodes E1, E2 to En disposed within two or more grooves
or channels carved in the sides of the reference electrode R
(parallel to the axis of the reference electrode R). The grooves
are sized such that the electrodes E1, E2 can snuggly fit therein.
Additionally, the depth of the grooves can be configured that the
electrode placed therein is externally exposed to a greater or
lesser degree. For example, the opening to the groove may be wider
or narrower. In some embodiments, a portion of an electrode
protrudes from the groove in which the electrode has been disposed.
In some embodiments, an insulator (e.g., I) takes the place of a
reference electrode (which can be disposed elsewhere, such remotely
as described in more detail elsewhere herein). The reference
electrode/insulator R/I can take any geometric structure known in
the art, such as but not limited to cylinders, rectangles, cones,
and the like. Similarly, the relative sizes of the working
electrodes E1, E2 and the reference electrode/insulator R/I can be
varied to achieve a desired signal level, to enable the use of the
desired voltage (e.g., to bias the sensor), and the like, as
described herein.
In one exemplary embodiment, a diffusion barrier D (described in
greater detail below) separates the working electrodes. The
diffusion barrier can be spatial, physical, or temporal. For
example, the distance around the reference electrode (e.g., from
the first working electrode E1 to the second working electrode E2,
around a portion of the circumference of the reference electrode R)
acts as a spatial diffusion barrier. In one exemplary embodiment,
the working electrodes are coated with a layer of insulating
material I (e.g., non-conductive material or dielectric) to prevent
direct contact between the working electrodes E1, E2 and the
reference electrode R. A portion of the insulator I on an exterior
surface of each working electrode is etched away, to expose the
electrode's electroactive surface. In some embodiments, an enzyme
solution (e.g., containing active GOx) is applied to the
electroactive surfaces of both electrodes, and dried. Thereafter,
the enzyme applied to one of the electroactive surfaces is
inactivated. As is known in the art, enzymes can be inactivated by
a variety of means, such as heat, treatment with inactivating
(e.g., denaturing) solvents, proteolysis, laser irradiation or UV
irradiation (e.g., at 254-320 nm). For example, the enzyme coating
one of the electroactive surfaces can be inactivated by masking one
of the electroactive surfaces/electrodes (e.g., E1, temporarily
covered with a UV-blocking material); irradiating the sensor with
UV light (e.g., 254-320 nm; a wavelength that inactivates the
enzyme, such as by cross-linking amino acid residues) and removing
the mask. Accordingly, the GOx on E2 is inactivated by the UV
treatment, but the E1 GOx is still active due to the protective
mask. In other embodiments, an enzyme solution containing active
enzyme is applied to a first electroactive surface (e.g., E1) and
an enzyme solution containing either inactivated enzyme or no
enzyme is applied to the second electroactive surface (e.g., E2).
Accordingly, the enzyme-coated first electroactive surface (e.g.,
E1) detects analyte-related signal and non-analyte-related signal;
while the second electroactive surface (e.g., E2), which lacks
active enzyme, detects non-analyte-related signal. As described
herein, the sensor electronics can use the data collected from the
two working electrodes to calculate the analyte-only signal.
Although this exemplary embodiment illustrates one embodiment of an
integrally-formed sensor having a diffusion barrier D, one skilled
in the art appreciates a variety of alternative configurations,
such as but not limited to the embodiment shown in FIG. 7I. In this
exemplary embodiment, the reference electrode is formed of at least
two adjacent pieces shaped such that the working electrodes fill at
least some space between them. The at least two pieces can be any
shape known in the art, as described herein. In some embodiments,
the at least two pieces are symmetrical and/or mirror images of
each other, but one skilled in the art will recognize that this is
not a requirement. In various embodiments, an insulating material
can be coated on the working electrodes and/or the reference
electrode(s) to prevent contact there between. As described
elsewhere herein, the working electrodes can detect the same
analyte or separate analytes, or one of the working electrodes may
act as a counter electrode (e.g., auxiliary electrode). Although
this exemplary embodiment illustrates one example of a sensor
having a reference electrode R that is formed of at least two
pieces shaped such that the working electrodes fill at least some
space between the pieces, one skilled in the art appreciates that a
variety of sensor configurations are possible. For example, the
reference electrode can be formed of three or more pieces. In other
example, the sensor can be configured with more than two working
electrodes (e.g., 3, 4, or 5 working electrodes, or more).
FIG. 7J is a schematic view of an integrally formed sensor in yet
another embodiment. In this exemplary embodiment, the reference
electrode R is formed in any desired extruded geometry, such as an
approximate X-shape. Two or more working electrodes E1, E2 are
disposed on substantially opposing sides of the reference
electrode, with a diffusion barrier D between them. In this
embodiment, the diffusion barrier is a physical diffusion barrier,
namely the distance between the two working electrodes (e.g.,
around the reference electrode). In some embodiments, the
electrodes are bundled and held together by a wrapping of wire or
fiber. In other embodiments, the electrodes are twisted around the
lengthwise axis of the extruded X-shaped reference electrode, to
form a coaxial sensor. Although this exemplary embodiment
illustrates an integrally formed sensor, one skilled in the art
appreciates a variety of alternative configurations. For example,
furthering some embodiments, three or four working electrodes can
be disposed around the reference electrode (e.g., in the
indentations between the legs/arms of the X-shaped electrode). In
other embodiments, the reference electrode can be Y-shapes,
star-shaped, flower-shaped, scalloped, or any other convenient
shape with multiple substantially isolated sides. In some
embodiments, an insulating material I takes the place of the
reference electrode of FIG. 7J, which is remotely located. In an
alternative embodiment, a working electrode is replaced with a
counter electrode. As described elsewhere herein, the sensor
components are bifunctional. Namely, the electrodes and reference
electrode provide electrical conduction and the sensor's structure.
The reference electrode (or insulating material) provides a
physical diffusion barrier D. In addition to providing shape to the
sensor, the insulating material acts as insulator by preventing
direct electrical contact between the electrodes. Similarly, the
materials selected to construct the sensor determine the sensor's
flexibility. As described elsewhere, active enzyme is applied to
the electroactive surface of at least one working electrode (e.g.,
E1). In some embodiments, no enzyme (or inactivated enzyme) is
applied to the electroactive surface of a second working electrode
(e.g., E2). In an alternative embodiment, a second enzyme is
applied to the second working electrode (e.g., E2) such that the
sensor can measure the signals of two different analytes (e.g.,
glucose and aureate or oxygen). FIG. 7K is a schematic of a sensor
in another embodiment. In some preferred embodiments, the sensor is
configured to be integrally formed of two working electrodes. In
this exemplary embodiment, the sensor includes two electrodes E1,
E2 (e.g., metal wires), wherein each electrode is coated with a
non-conductive material I (e.g., and insulator). As is shown in
FIG. 7K, the first working electrode E1 formed within the insulator
I leaving space for an enzyme. For example, an enzyme solution 702
(e.g., GOx for detecting glucose) is disposed within the space 701.
In contrast, the second working electrode E2 extends substantially
flush with the insulator I. A membrane system 703 coats the
electrodes. A diffusion barrier D separates the working electrodes.
In some embodiments, the first and second electrodes are separated
by a distance D that substantially prevents diffusion of
H.sub.2O.sub.2 from the first electrode (e.g., with active enzyme)
to the second electrode (e.g., without active enzyme). Although
this exemplary embodiment illustrates one integrally formed sensor,
one skilled in the art appreciates a variety of alternative
configurations. For example, the use of more than two working
electrodes and wrapping the construct with a reference electrode
wire R or disposing the reference electrode remotely from the
sensor.
FIG. 7L is a schematic of a sensor in one embodiment. In some
preferred embodiments, the sensor is designed to be integrally
formed. In this exemplary embodiment, two electrodes E1, E2 are
embedded within an insulator I. The sensor can be formed by
embedding conductive wires within a dielectric, curing the
dielectric and then cutting sensors of the desired length. The cut
end provides the exposed electroactive electrode surfaces and can
be polished or otherwise treated. Although this exemplary
embodiment illustrates one integrally formed sensor, one skilled in
the art appreciates a variety of alternative configurations. For
example, additional electrode wires can be embedded in the
dielectric material. In another example, a reference electrode
(e.g., wire or cylinder) can be coiled or wrapped around the sensor
(e.g., on the surface of the insulator). Alternatively, as
described elsewhere herein, the reference electrode can be disposed
remotely from the working electrodes E1, E2, such as on the host's
skin or on another portion of the sensor. One advantage of this
configuration is that it is relatively simple to embed electrode
wires in a long cylinder of insulating material and then cut the
sensors to any desired size and/or shape.
FIG. 7M is a schematic cross-sectional view of a sensor having
multiple working and reference electrodes, in one embodiment. In
some preferred embodiments, the sensor is integrally formed. In
this exemplary embodiment, the sensor includes a plurality of
working electrodes (e.g., E1, E2, E3) that are layered with a
plurality of reference electrodes (e.g., R1, R2, Rn). In some
embodiments, the working electrodes are coated with an insulating
material to prevent direct contact with adjacent reference
electrodes. In some embodiments, the reference electrodes are also
coated with insulative material. In some embodiments, layers of
insulating material separate the layers. In some embodiments, at
least one of the working electrodes is a counter electrode. As
described herein, in some embodiments, electroactive surfaces are
exposed on one or more electrodes, such as by stripping away a
portion of an insulating coating, such as on the sides of the
sensor. In other embodiments, an extended electrode structure
(e.g., a long sandwich of electrode layers) that is cut to the
desired length, and the cut end includes the exposed electroactive
surfaces of the electrodes. An enzyme layer can be applied to one
or more of the electroactive surfaces, as described herein.
Depending upon the desired sensor function, the working electrodes
can be configured to detect the same analyte (e.g., all
electroactive surfaces coated with GOx glucose) or different
analytes (e.g., one working electrode detects glucose, another
detects oxygen and the third detects aureate), as described herein.
Although this exemplary embodiment illustrates a sensor having a
plurality of working and reference electrodes, one skilled in the
art appreciates a variety of alternative configurations. For
example, in some embodiments, the electrodes can be of various
sizes, depending upon their purpose. For example, in one sensor, it
may be preferred to use a 3 mm oxygen electrode, a 10 mm glucose
electrode and a 4 mm counter electrode, all separated by reference
electrodes. In another embodiment, each reference electrode can be
functionally paired with a working electrode. For example, the
electrodes can be pulsed on and off, such that a first reference
electrode R1 is active only when the first working electrode E1 is
active, and a second reference electrode R2 is active only when the
second working electrode E2 is active. In another embodiment, a
flat sensor (e.g., disk-shaped) can be manufactured by sandwiching
reference electrodes between working electrodes, cutting the
sandwich into a cylinder, and the cutting the cylinder cross-wise
(perpendicularly or at an angle) into disks.
FIG. 7N is a schematic cross-sectional view of the manufacture of
an integrally formed sensor, in one embodiment. In some preferred
embodiments, at least two working electrodes (E1, E2) and
optionally a reference electrode R are embedded in a quantity 704
of insulating material I. The working electrodes are separated by a
diffusion barrier D. After the insulator has been cured (e.g.,
vulcanized or solidified) the structure is shaped (e.g., carved,
scraped or cut etc.) to the final sensor shape 705, such that
excess insulation material is removed. In some embodiments,
multiple sensors can be formed as an extended structure of
electrode wires embedded in insulator, which is subsequently cut to
the desired length, wherein the exposed electrode ends (e.g., at
the cut surface) become the electroactive surfaces of the
electrodes. In other embodiments, portions of the insulator
adjacent to the electrodes (e.g., windows) can be removed (e.g., by
cutting or scraping, etc.) to expose the electroactive surfaces.
Depending upon the sensor's configuration and purpose, an enzyme
solution can be applied to one or more of the electroactive
surfaces, as described elsewhere herein. Although this exemplary
embodiment illustrates one technique of manufacturing a sensor
having insulation-embedded electrodes, one skilled in the art
appreciates a variety of alternative configurations. For example, a
diffusion barrier D, can comprise both the reference electrode R
and the insulating material I, or only the reference electrode. In
another example, windows exposing the electroactive surfaces can be
formed adjacent to each other (e.g., on the same side of the
reference electrode) or on opposite sides of the reference
electrode. Still, in other embodiments, more working or reference
electrodes can be included, and the working and reference
electrodes can be of relatively larger or smaller size, depending
upon the sensor's configuration and operating requirements (e.g.,
voltage and/or current requirements).
FIGS. 8A and 8B are schematic views of a sensor in yet another
embodiment. FIG. 8A is a view of the cross-section and side of an
in vivo portion of the sensor. FIG. 8B is a side view of the ex
vivo portion of the sensor (e.g., the portion that is connected to
the sensor electronics, as described elsewhere herein). Namely, two
working electrodes E1, E2 that are coated with insulator I and then
disposed on substantially opposing sides of a reference electrode
R, such as a silver or silver/silver chloride electrode (see FIG.
8A). The working electrodes are separated by a diffusion barrier D
that can include a physical barrier (provided by the reference
electrode and/or the insulating material coatings), a spatial
barrier (provided by staggering the electroactive surfaces of the
working electrodes), or a temporal barrier (provided by oscillating
the potentials between the electrodes). In some embodiments, the
reference electrode R has a surface area at least 6-times the
surface area of the working electrodes. Additionally, the reference
electrode substantially can act as a spatial diffusion barrier
between the working electrodes due to its larger size (e.g., the
distance across the reference electrode, from one working electrode
to another).
The electrodes can be held in position by wrapping with wire or a
non-conductive fiber, a non-conductive sheath, a biointerface
membrane coating, or the like. The electroactive surfaces of the
working electrodes are exposed. In some embodiments, the end of the
sensor is cut off, to expose the ends of the wires. In other
embodiments, the ends of the wires are coated with insulating
material; and the electroactive surfaces are exposed by removing a
portion of the insulating material (e.g., a window 802 cut into the
side of the insulation coating the electrode). In some embodiments,
the windows exposing the electroactive surfaces of the electrodes
can be staggered (e.g., spaced such that one or more electrodes
extends beyond the other one or more electrodes), symmetrically
arranged or rotated to any degree; for example, to substantially
prevent diffusion of electroactive species from one working
electrode (e.g., 802a) to the other working electrode (e.g., 802b),
as will be discussed in greater detail elsewhere herein. In various
embodiments, the reference electrode is not coated with a
nonconductive material. The reference electrode can have a surface
area that is at least 6 times the surface area of the exposed
working electrode electroactive surfaces. In some embodiments, the
reference electrode R surface area is 7-10 times (or larger) than
the surface area of the working electrode electroactive surfaces.
In still other embodiments, the reference electrode can be only 1-5
times the surface area of working electrode electroactive surfaces
(e.g., (E1+E2).times.1=R or (E1+E2).times.2=R, etc.).
The ex vivo end of the sensor is connected to the sensor
electronics (not shown) by electrical connectors 804a, 804b, 804c.
In some embodiments, the ex vivo end of the sensor is stepped. For
example, the ex vivo end of the reference electrode R terminates
within electrical connector 804a. The ex vivo end of the first
working electrode E1 is exposed (e.g., nonconductive material
removed therefrom) and terminates a small distance past the
reference electrode R, within electrical connector 804b. Similarly,
the ex vivo end of the second working electrode E2 is exposed
(e.g., nonconductive material removed therefrom) and terminates a
small distance past the termination of the first working electrode
E1, within electrical connector 804c.
Although this exemplary embodiment illustrates one configuration of
an integrally formed sensor, one skilled in the art appreciates a
variety of alternative configurations. For example, in some
embodiments, a portion of the in vivo portion of the sensor can be
twisted and/or stepped. More working, reference, and/or counter
electrodes, as well as insulators, can be included. The electrodes
can be of relatively larger or smaller size, depending upon the
sensor's intended function. In some embodiments, the electroactive
surfaces can be staggered. In still other embodiments, the
reference electrode can be disposed remotely from the sensor, as
described elsewhere herein. For example, the reference electrode
shown in FIG. 8A can be replaced with a non-conductive support and
the reference electrode disposed on the host's skin.
With reference to the ex vivo portion of the sensor, one skilled in
the art appreciates additional alternative configurations. For
example, in one embodiment, a portion of the ex vivo portion of the
sensor can be twisted or coiled. In some embodiments, the working
and reference electrodes can be of various lengths and
configurations not shown in FIG. 8B. For example, the reference
electrode R can be the longest (e.g., connect to electrical contact
804c) and the first second working electrode E2 can be the shortest
(e.g., connect to electrical contact 804a). In other embodiments,
the first working electrode E1 may be either the longest electrode
(e.g., connect to electrical contact 804c) or the shortest
electrode (e.g., connect to electrical contact 804a).
FIG. 9A is a schematic view that illustrates yet another exemplary
embodiment of an integrally formed analyte sensor. Namely, two
working electrodes E1, E2 are bundled together and substantially
encircled with a cylindrical silver or silver/silver chloride
reference electrode R (or the like). The reference electrode can be
crimped at a location 902, to prevent movement of the working
electrodes E1, E2 within the reference electrode R cylinder. In
alternative embodiments, a reference electrode can be rolled or
coiled around the working electrodes E1, E2, to form the reference
electrode R. Preferably, the working electrodes are at least
partially insulated as described in more detail elsewhere herein;
such as by coating with a non-conductive material, such as but not
limited to Parylene. One skilled in the art appreciates that a
variety of alternative configurations are possible.
FIG. 9B illustrates another embodiment of an integrally formed
analyte sensor. Namely, two working electrodes E1, E2 are bundled
together with a silver or silver/silver chloride wire reference
electrode R coiled there around. The reference electrode can be
coiled tightly, to prevent movement of the working electrodes E1,
E2 within the reference electrode R coil.
Referring again to FIGS. 9A to 9B, near the tip of the in vivo
portion of the sensor, windows 904a and 904b are formed on the
working electrodes E1, E2. Portions of the non-conductive material
(e.g., insulator) coating each electrode is removed to form windows
904a and 904b. The electroactive surfaces of the electrodes are
exposed via windows 904a and 904b. As described elsewhere herein,
the electrode electroactive surfaces exposed through windows 904a
and 904b are coated with a membrane system. An active enzyme (e.g.,
GOx is used if glucose is the analyte) is disposed within or
beneath or within the membrane covering one of the windows (e.g.,
904a or 904b). The membrane covering the other window can include
inactivated enzyme (e.g., GOx inactivated by heat, solvent, UV or
laser irradiation, etc., as described herein) or no enzyme. The
electrode having active enzyme detects a signal related to the
analyte concentration and non-analyte related signal (e.g., due to
background, etc.). In contrast, the electrode having inactive
enzyme or no enzyme detects substantially only the non-analyte
related signal. These signals are transmitted to sensor electronics
(discussed elsewhere herein) to calculate an analyte concentration
based on only the signal component related to only the analyte
(described elsewhere herein).
In general, the windows 904a and 904b are separated or staggered by
a distance D, which is selected to be sufficiently large that
electroactive species (e.g., H.sub.2O.sub.2) do not substantially
diffuse from one window to the other (e.g., from 904a to 904b). In
an exemplary embodiment of a glucose-oxidase-based sensor, active
enzyme is included in the membrane covering window 904a and
inactive enzyme is included in the membrane covering window 904b.
Distance D is configured to be large enough that H.sub.2O.sub.2
cannot diffuse from window 904a to window 904b, which lacks active
enzyme (as discussed elsewhere herein). In some embodiments, the
distance D is at least about 0.020 inches or less to about 0.120
inches or more. In some embodiments, D is at least about 0.030 to
about 0.050 inches. In other embodiments, D is at least about 0.090
to about 0.095 inches. One skilled in the art appreciates
alternative embodiments of the diffusion barrier D. Namely, the
diffusion barrier D can be spatial (discussed herein with relation
to FIGS. 9A and 9B), physical or temporal (see discussion of
Diffusion Barriers herein and FIG. 10). In some embodiments, a
physical diffusion barrier D, such as but not limited to an
extended non-conductive structure placed between the working
electrodes (e.g., FIG. 8A), substantially prevents diffusion of
H.sub.2O.sub.2 from one working electrode (having active enzyme) to
another working electrode (having no active enzyme). In other
embodiments, a temporal diffusion barrier D is created by pulsing
or oscillating the electrical potential, such that only one working
electrode is activated at a time.
In various embodiments, one of the windows 904a or 904b comprises
an enzyme system configured to detect the analyte of interest
(e.g., glucose or oxygen). The other window comprises no active
enzyme system (e.g., wherein the enzyme system lacks enzyme or
wherein the enzyme has been de-activated). In some embodiments,
wherein the "enzyme system lacks enzyme," a layer may be applied,
similar to an active enzyme layer, but without the actual enzyme
included therein. In some embodiments, wherein "the enzyme has been
de-activated" the enzyme can be inactivated (e.g., by heat or
solvent) prior to addition to the enzyme system solution or the
enzyme can be inactivated after application to the window.
In one exemplary embodiment, an enzyme is applied to both windows
904a and 904b followed by deactivation of the enzyme in one window.
For example, one window can be masked (e.g., to protect the enzyme
under the mask) and the sensor then irradiated (to deactivate the
enzyme in the unmasked window). Alternatively, one of the
enzyme-coated windows (e.g., the first window but not the second
window) can be sprayed or dipped in an enzyme-deactivating solvent
(e.g., treated with a protic acid solution such a hydrochloric acid
or sulfuric acid). For example, a window coated with GOx can be
dipped in dimethyl acetamide (DMAC), ethanol, or tetrahydrofuran
(THF) to deactivate the GOx. In another example, the enzyme-coated
window can be dipped into a hot liquid (e.g., water or saline) to
deactivate the enzyme with heat.
In these embodiments, the design of the active and inactive enzyme
window is at least partially dependent upon the sensor's intended
use. In some embodiments, it is preferred to deactivate the enzyme
coated on window 904a. In other embodiments, it is preferred to
deactivate the enzyme coated on window 904b. For example, in the
case of a sensor to be used in a host's blood stream, the choice
depends upon whether the sensor will be inserted pointing upstream
(e.g., against the blood flow) or pointing downstream (e.g., with
the blood flow).
In one exemplary embodiment, an intravascular sensor is inserted
into the host's vein pointing upstream (against the blood flow), an
enzyme coating on electrode E1 (window 904a) is inactivated (e.g.,
by dipping in THF and rinsing) and an enzyme coating on electrode
E2 (in window 904b) is not inactivated (e.g., by not dipping in
THF). Because the enzyme on the first electrode E1 (e.g., in window
904a) is inactive, electroactive species (e.g., H.sub.2O.sub.2)
will not be substantially generated at window 904a (e.g., the first
electrode E1 generates substantially no H.sub.2O.sub.2 to effect
the second electrode E2). In contrast, the active enzyme on the
second electrode E2 (in window 904b) generates H.sub.2O.sub.2 which
at least partially diffuses down stream (away from the windows) and
thus has no effect on the first electrode E1, other features and
advantages of spatial diffusion barriers are described in more
detail elsewhere herein.
In another exemplary embodiment, an intravascular sensor is
inserted into the host's vein pointing downstream (with the blood
flow), the enzyme coating on electrode E1 (window 904a) is active
and the enzyme coating on electrode E2 (in window 904b) is
inactive. Because window 904a is located farther downstream than
window 904b, the H.sub.2O.sub.2 produced by the enzyme in 904a
diffuses downstream (away from window 904b), and therefore does not
affect substantially electrode E2. In a preferred embodiment, the
enzyme is GOx, and the sensor is configured to detect glucose.
Accordingly, H.sub.2O.sub.2 produced by the GOx in window 904a does
not affect electrode E2, because the sensor is pointing downstream
and the blood flow carries away the H.sub.2O.sub.2 produced on
electrode E1.
FIGS. 9A and 9B illustrate two embodiments of a sensor having a
stepped second end (e.g., the back end, distal end or ex vivo end,
described with reference to FIG. 8B) that connects the sensor to
the sensor electronics. Namely, each electrode terminates within an
electrical connector 804 such as but not limited to an elastomeric
electrical connector. Additionally, each electrode is of a
different length, such that each electrode terminates within one of
a plurality of sequential electrical connectors. For example, with
reference to FIG. 9A, the reference electrode R is the shortest in
length and terminates within the first electrical connector 804.
The first working electrode E1 is longer than the reference
electrode R, and terminates within the second electrical connector
804. Finally, the second working electrode E2 is the longest
electrode and terminates within the third electrical connector 804.
One skilled in the art appreciates that other configurations are
possible. For example, the first working electrode E1 can be longer
than the second working electrode E2. Accordingly, the second
working electrode E2 would terminate within the second (e.g.,
middle) electrical connector 804 and the first working electrode E1
would terminate within the third (e.g., last) electrical connector
804. With reference to FIG. 9B, additional stepped second end
configurations are possible. In alternative embodiments, the second
ends of the sensor may be separated from each other to connect to
non-parallel, non-sequential electrical connectors.
FIG. 11 is a schematic view of a sensor in yet another embodiment.
In preferred embodiments, the sensor is integrally formed, coaxial,
and has a stepped ex vivo end (e.g., back or second end).
Electrodes E1, E2 and E3 are twisted to form a helix, such as a
triple helix. Additionally, at the back end of the sensor, the
electrodes are stepped and each electrode is individually connected
to the sensor electronics by an electrical connector 804. At each
electrode's second end, the electrode engages an electrical
connector 804 that joins the electrode to the sensor electronics.
For example, the second end of electrode E1 electrically connects
electrical connector 1106. Similarly, the second end of electrode
E2 electrically connects electrical connector 1108 and the second
end of electrode E3 electrically connects electrical connector
1110. As described elsewhere herein, each sensor component is
difunctional, and provides electrical conductance, structural
support, a diffusion barrier, or insulation (see description
elsewhere herein). Although this exemplary embodiment illustrates
an integrally formed, coaxial sensor having a stepped back end, one
skilled in the art appreciates a variety of alternative
configurations. For example, one of the electrodes E1, E2 or E3 can
be a reference electrode, or the reference electrode can be
disposed remotely from the sensor, such as but not limited to on
the host's skin. In another example, the sensor can have only two
electrodes or more than three electrodes.
One skilled in the art recognizes a variety of alternative
configurations for the embodiments described herein. For example,
in any embodiment of an analyte sensor, the reference electrode
(and optionally a counter electrode) can be disposed remotely from
the working electrodes. For example, in FIGS. 7A1 through 9B and
FIG. 11, the reference electrode R can be replaced with a
non-conductive material, such as an insulator I. Depending upon the
sensor's configuration and location of use, the reference electrode
R can then be inserted into the host in a location near to the
sensor, applied to the host's skin, be disposed within a fluid
connector, be disposed on the ex-vivo portion of the sensor or even
disposed on the exterior of the sensor electronics.
FIG. 7L illustrates an embodiment in which the reference and/or
counter electrode is located remotely from the first and second
working electrodes E1 and E2, respectively. In one exemplary
embodiment, the sensor is a needle-type sensor such as described
with reference to FIG. 1B, and the working electrodes E1, E2 are
integrally formed together with a substantially X-shaped insulator
I and the reference electrode (and/or counter electrode) is placed
on the host's skin (e.g., a button, plate, foil or wire, such as
under the housing) or implanted transcutaneously in a location
separate from the working electrodes.
As another example, in one embodiment of a sensor configured to
measure a host's blood, such as described in co-pending U.S. patent
application Ser. Nos. 11/543,396, 11/543,490, and 11/543,404 [Pub.
Nos. 2008-0119703 A1, 2008-0119704 A1, 2008-0119706 A1], entitled
"Analyte sensor" and filed Oct. 4, 2006, and which is incorporated
herein by reference in its entirety; one or more working electrodes
can be inserted into the host's blood via a catheter and the
reference and/or counter electrode can be placed within the a fluid
connector (on the sensor) configured to be in fluid communication
with the catheter; in such an example, the reference and/or counter
electrode is in contact with fluid flowing through the fluid
connector but not in direct contact with the host's blood. In still
other embodiments, the reference and/or counter electrodes can be
placed exterior to the sensor, in bodily contact for example.
With reference to the analyte sensor embodiments disclosed herein,
the surface area of the electroactive portion of the reference
(and/or counter) electrode is at least six times the surface area
of one or more working electrodes. In other embodiments, the
reference (and/or counter) electrode surface is 1, 2, 3, 4, 5, 7,
8, 9 or 10 times the surface area of the working electrodes. In
other embodiments, the reference (and/or counter) electrode surface
area is 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 times the surface
area of the working electrodes. For example, in a needle-type
glucose sensor, similar to the embodiment shown in FIG. 1B, the
surface area of the reference electrode (e.g., 18 or 20) includes
the exposed surface of the reference electrode, such as but not
limited to the electrode surface facing away from the working
electrode 16.
In various embodiments, the electrodes can be stacked or grouped
similar to that of a leaf spring configuration, wherein layers of
electrode and insulator (or individual insulated electrodes) are
stacked in offset layers. The offset layers can be held together
with bindings of non-conductive material, foil, or wire. As is
appreciated by one skilled in the art, the strength, flexibility,
and/or other material property of the leaf spring-configured or
stacked sensor can be either modified (e.g., increased or
decreased), by varying the amount of offset, the amount of binding,
thickness of the layers, and/or materials selected and their
thicknesses, for example.
In some embodiments, the sensor (e.g., a glucose sensor) is
configured for implantation into the host. For example, the sensor
may be wholly implanted into the host, such as but not limited to
in the host's subcutaneous tissue (e.g., the embodiment shown in
FIG. 1A). In other embodiments, the sensor is configured for
transcutaneous implantation in the host's tissue. For example, the
sensor can have a portion that is inserted through the host's skin
and into the underlying tissue, and another portion that remains
outside the host's body (e.g., such as described in more detail
with reference to FIG. 1B). In still other embodiments, the sensor
is configured for indwelling in the host's blood stream. For
example, a needle-type sensor can be configured for insertion into
a catheter dwelling in a host's vein or artery. In another example,
the sensor can be integrally formed on the exterior surface of the
catheter, which is configured to dwell within a host's vein or
artery. Examples of indwelling sensors can be found in co-pending
U.S. patent application Ser. Nos. 11/543,396, 11/543,490, and
11/543,404 [Pub. Nos. 2008-0119703 A1, 2008-0119704 A1,
2008-0119706 A1], entitled "Analyte sensor" and filed Oct. 4, 2006.
In various embodiments, the in vivo portion of the sensor can take
alternative configurations, such as but not limited to those
described in more detail with reference to FIGS. 7A-9B and 11.
In preferred embodiments, the analyte sensor substantially
continuously measures the host's analyte concentration. In some
embodiments, for example, the sensor can measure the analyte
concentration every fraction of a second, about every fraction of a
minute or every minute. In other exemplary embodiments, the sensor
measures the analyte concentration about every 2, 3, 4, 5, 6, 7, 8,
9, or 10 minutes. In still other embodiments, the sensor measures
the analyte concentration every fraction of an hour, such as but
not limited to every 15, 30 or 45 minutes. Yet in other
embodiments, the sensor measures the analyte concentration about
every hour or longer. In some exemplary embodiments, the sensor
measures the analyte concentration intermittently or periodically.
In one preferred embodiment, the analyte sensor is a glucose sensor
and measures the host's glucose concentration about every 4-6
minutes. In a further embodiment, the sensor measures the host's
glucose concentration every 5 minutes.
In one exemplary embodiment, the analyte sensor is a glucose sensor
having a first working electrode configured to generate a first
signal associated with both glucose and non-glucose related
electroactive compounds that have a first oxidation potential.
Non-glucose related electroactive compounds can be any compound, in
the sensor's local environment that has an oxidation potential
substantially overlapping with the oxidation potential of
H.sub.2O.sub.2, for example. While not wishing to be bound by
theory, it is believed that the glucose-measuring electrode can
measure both the signal directly related to the reaction of glucose
with GOx (produces H.sub.2O.sub.2 that is oxidized at the working
electrode) and signals from unknown compounds that are in the
extracellular milieu surrounding the sensor. These unknown
compounds can be constant or non-constant (e.g., intermittent or
transient) in concentration and/or effect. In some circumstances,
it is believed that some of these unknown compounds are related to
the host's disease state. For example, it is know that blood
chemistry changes dramatically during/after a heart attack (e.g.,
pH changes, changes in the concentration of various blood
components/protein, and the like). Other compounds that can
contribute to the non-glucose related signal are believed to be
related to the wound healing process that is initiated by
implantation/insertion of the sensor into the host, which is
described in more detail with reference to co-pending U.S. patent
application Ser. No. 11/503,367 filed Aug. 10, 2006 and entitled
"ANALYTE SENSOR," which is incorporated herein by reference in its
entirety. For example, transcutaneously inserting a needle-type
sensor initiates a cascade of events that includes the release of
various reactive molecules by macrophages.
In some embodiments, the glucose sensor includes a second (e.g.,
auxiliary) working electrode that is configured to generate a
second signal associated with non-glucose related electroactive
compounds that have the same oxidation potential as the
above-described first working electrode (e.g., para supra). In some
embodiments, the non-glucose related electroactive species includes
at least one of interfering species, non-reaction-related
H.sub.2O.sub.2, and other electroactive species. For example,
interfering species includes any compound that is not directly
related to the electrochemical signal generated by the glucose-GOx
reaction, such as but not limited to electroactive species in the
local environment produces by other bodily processes (e.g.,
cellular metabolism, wound healing, a disease process, and the
like). Non-reaction-related H.sub.2O.sub.2 includes H.sub.2O.sub.2
from sources other than the glucose-GOx reaction, such as but not
limited to H.sub.2O.sub.2 released by nearby cells during the
course of the cells' metabolism, H.sub.2O.sub.2 produced by other
enzymatic reactions (e.g., extracellular enzymes around the sensor
or such as can be released during the death of nearby cells or such
as can be released by activated macrophages), and the like. Other
electroactive species includes any compound that has an oxidation
potential similar to or overlapping that of H.sub.2O.sub.2.
The non-analyte (e.g., non-glucose) signal produced by compounds
other than the analyte (e.g., glucose) obscured the signal related
to the analyte, contributes to sensor inaccuracy, and is considered
background noise. As described in greater detail in the section
entitled "Noise Reduction," background noise includes both constant
and non-constant components and must be removed to accurately
calculate the analyte concentration. While not wishing to be bound
by theory, it is believed that the sensor of the preferred
embodiments are designed (e.g., with symmetry, coaxial design
and/or integral formation) such that the first and second
electrodes are influenced by substantially the same
external/environmental factors, which enables substantially
equivalent measurement of both the constant and non-constant
species/noise. This advantageously allows the substantial
elimination of noise (including transient biologically related
noise that has been previously seen to affect accuracy of sensor
signal due to it's transient and unpredictable behavior) on the
sensor signal (using electronics described elsewhere herein) to
substantially reduce or eliminate signal effects due to noise,
including non-constant noise (e.g., unpredictable biological,
biochemical species or the like) known to effect the accuracy of
conventional continuous sensor signals. Preferably, the sensor
includes electronics operably connected to the first and second
working electrodes. The electronics are configured to provide the
first and second signals that are used to generate glucose
concentration data substantially without signal contribution due to
non-glucose-related noise. Preferably, the electronics include at
least a potentiostat that provides a bias to the electrodes. In
some embodiments, sensor electronics are configured to measure the
current (or voltage) to provide the first and second signals. The
first and second signals are used to determine the glucose
concentration substantially without signal contribution due to
non-glucose-related noise such as by but not limited to subtraction
of the second signal from the first signal or alternative data
analysis techniques. In some embodiments, the sensor electronics
include a transmitter that transmits the first and second signals
to a receiver, where additional data analysis and/or calibration of
glucose concentration can be processed. U.S. Publication Nos.
US-2005-0027463-A1, US-2005-0203360-A1 and US-2006-0036142-A1
describe systems and methods for processing sensor analyte data and
are incorporated herein by reference in their entirety.
In preferred embodiments, the sensor electronics (e.g., electronic
components) are operably connected to the first and second working
electrodes. The electronics are configured to calculate at least
one analyte sensor data point. For example, the electronics can
include a potentiostat, A/D converter, RAM, ROM, transmitter, and
the like. In some embodiments, the potentiostat converts the raw
data (e.g., raw counts) collected from the sensor to a value
familiar to the host and/or medical personnel. For example, the raw
counts from a glucose sensor can be converted to milligrams of
glucose per deciliter of glucose (e.g., mg/dl). In some
embodiments, the electronics are operably connected to the first
and second working electrodes and are configured to process the
first and second signals to generate a glucose concentration
substantially without signal contribution due to non-glucose noise
artifacts. The sensor electronics determine the signals from
glucose and non-glucose related signal with an overlapping
measuring potential (e.g., from a first working electrode) and then
non-glucose related signal with an overlapping measuring potential
(e.g., from a second electrode). The sensor electronics then use
these data to determine a substantially glucose-only concentration,
such as but not limited to subtracting the second electrode's
signal from the first electrode's signal, to give a signal (e.g.,
data) representative of substantially glucose-only concentration,
for example. In general, the sensor electronics may perform
additional operations, such as but not limited to data smoothing
and noise analysis.
Bifunctionality
In some embodiments, the components of at least a portion (e.g.,
the in vivo portion or the sensing portion) of the sensor possess
bifunctional properties (e.g., provide at least two functions to
the sensor). These properties can include electrical conductance,
insulative properties, structural support, and diffusion barrier
properties.
In one exemplary embodiment, the analyte sensor is designed with
two working electrodes, a membrane system and an insulating
material disposed between the working electrodes. An active
enzymatic membrane is disposed above the first working electrode,
while an inactive- or non-enzymatic membrane is disposed above the
second working electrode. Additionally, the working electrodes and
the insulating material are configured provide at least two
functions to the sensor, including but not limited to electrical
conductance, insulative properties, structural support, and
diffusion barrier. For example, in one embodiment of a glucose
sensor, the two working electrodes support the sensor's structure
and provide electrical conductance; the insulating material
provides insulation between the two electrodes and provides
additional structural support and/or a diffusional barrier.
In some embodiments, a component of the sensor is configured to
provide both electrical conductance and structural support. In an
exemplary embodiment, the working electrode(s) and reference
electrode are generally manufactured of electrically conductive
materials, such as but not limited silver or silver/silver
chloride, copper, gold, platinum, iridium, platinum-iridium,
palladium, graphite, carbon, conductive polymers, alloys, and the
like. Accordingly, the electrodes are both conductive and they give
the sensor its shape (e.g., are supportive).
Referring to FIG. 1B, all three electrodes 16, 18, and 20 are
manufactured from plated insulator, a plated wire, or electrically
conductive material, such as but not limited to a metal wire.
Accordingly, the three electrodes provide both electrical
conductance (to measure glucose concentration) and structural
support. Due to the configuration of the electrodes (e.g., the
wires are about 0.001 inches in diameter or less, to about 0.01
inches or more), the sensor is needle-like and only about 0.003
inches or less to about 0.015 inches or more.
Similarly, the electrodes of FIG. 7A through FIG. 9 provide
electrical conductance, to detect the analyte of interest, as well
as structural support for the sensor. For example, the sensors
depicted in FIGS. 7A through 7L embodiments that are substantially
needle-like. Additionally, these sensors are substantially
resilient, and therefore able to flex in response to mechanical
pressure and then to regain their original shapes. FIG. 7M depicts
a cross-section of another sensor embodiment, which can be a
composite (e.g., built up of layers of working and reference
electrode materials) needle-like sensor or the composite "wire" can
be cut to produce pancake-shaped sensors. FIG. 7N through FIG. 9
illustrate additional sensor embodiments, wherein the electrodes
provide electrical conductance and support the sensor's needle-like
shape.
In some embodiments, the first and second working electrodes are
configured to provide both electrical conductance and structural
support. For example, in a needle-type sensor, the working
electrodes are often manufactured of bulk metal wires (e.g.,
copper, gold, platinum, iridium, platinum-iridium, palladium,
graphite, carbon, conductive polymers, alloys, and the like). The
reference electrode, which can function as a reference electrode
alone, or as a dual reference and counter electrode, are formed
from silver or silver/silver chloride, or the like. The metal wires
are conductive (e.g., can conduct electricity) and give the sensor
its shape and/or structural support. For example, one electrode
metal wire may be coiled around the other electrode metal wire
(e.g., FIG. 1B or FIG. 7B). In a further embodiment, the sensor
includes a reference electrode that is also configured to provide
electrical conductance and structural support (e.g., FIG. 1B, FIGS.
7C to 7E). In general, reference electrodes are made of metal, such
as bulk silver or silver/silver chloride wires. Like the two
working electrodes, the reference electrode both conducts
electricity and supports the structure of the sensor.
In some embodiments, the first and second working electrode and the
insulating material are configured provide at least two functions,
such as but not limited to electrical conductance, insulative
properties, structural support, and diffusion barrier. As described
elsewhere herein, the working electrodes are electrical conductors
and also provide support for the sensor. The insulating material
(e.g., I) acts as an insulator, to prevent electrical communication
between certain parts of the various electrodes. The insulating
material also provides structural support or substantially prevents
diffusion of electroactive species from one working electrode to
the other, which is discussed in greater detail elsewhere
herein.
In preferred embodiments, the sensor has a diffusion barrier
disposed between the first and second working electrodes. The
diffusion barrier is configured to substantially block diffusion of
the analyte or a co-analyte (e.g., H.sub.2O.sub.2) between the
first and second working electrodes. For example, a sheet of a
polymer through which H.sub.2O.sub.2 cannot diffuse can be
interposed between the two working electrodes. Diffusion barriers
are discussed in greater detail elsewhere herein.
In some embodiments of the preferred embodiments, the analyte
sensor includes a reference electrode that is configured to provide
electrical conductance and a diffusion barrier. Electrical
conductance is an inherent property of the metal used to
manufacture the reference electrode. However, the reference
electrode can be configured to prevent species (e.g.,
H.sub.2O.sub.2) from diffusing from the first working electrode to
the second working electrode. For example, a sufficiently large
reference electrode can be placed between the two working
electrodes. In some embodiments, the reference electrode projects
farther than the two working electrodes. In other embodiments, the
reference electrode is so broad that a substantial portion of the
H.sub.2O.sub.2 produced at the first working electrode cannot
diffuse to the second working electrode, and thereby significantly
affect the second working electrode's function.
In a further embodiment, the reference electrode is configured to
provide a diffusion barrier and structural support. As described
elsewhere herein, the reference electrode can be constructed of a
sufficient size and/or shape that a substantial portion of the
H.sub.2O.sub.2 produced at a first working electrode cannot diffuse
to the second working electrode and affect the second working
electrode's function. Additionally, metal wires are generally
resilient and hold their shape, the reference electrode can also
provide structural support to the sensor (e.g., help the sensor to
hold its shape).
In some embodiments of the analyte sensor described elsewhere
herein, the insulating material is configured to provide both
electrical insulative properties and structural support. In one
exemplary embodiment, portions of the electrodes are coated with a
non-conductive polymer. Inherently, the non-conductive polymer
electrically insulates the coated electrodes from each other, and
thus substantially prevents passage of electricity from one coated
wire to another coated wire. Additionally, the non-conductive
material (e.g., a non-conductive polymer or insulating material)
can stiffen the electrodes and make them resistant to changes in
shape (e.g., structural changes).
In some embodiments, a sensor component is configured to provide
electrical insulative properties and a diffusion barrier. In one
exemplary embodiment, the electrodes are coated with the
non-conductive material that substantially prevents direct contact
between the electrodes, such that electricity cannot be conducted
directly from one electrode to another. Due to the non-conductive
coatings on the electrodes, electrical current must travel from one
electrode to another through the surrounding aqueous medium (e.g.,
extracellular fluid, blood, wound fluid, or the like). Any
non-conductive material (e.g., insulator) known in the art can be
used to insulate the electrodes from each other. In exemplary
embodiments, the electrodes can be coated with non-conductive
polymer materials (e.g., parylene, PTFE, ETFE, polyurethane,
polyethylene, polyimide, silicone and the like) by dipping,
painting, spraying, spin coating, or the like.
Non-conductive material (e.g., insulator, as discussed elsewhere
herein) applied to or separating the electrodes can be configured
to prevent diffusion of electroactive species (e.g.,
H.sub.2O.sub.2) from one working electrode to another working
electrode. Diffusion of electroactive species from one working
electrode to another can cause a false analyte signal. For example,
electroactive species (e.g., H.sub.2O.sub.2) that are created at a
first working electrode having active enzyme (e.g., GOx) can
diffuse to a nearby working electrode (e.g., without active GOx).
When the electroactive species arrives at the second working
electrode, the second electrode registers a signal (e.g., as if the
second working electrode comprised active GOx). The signal
registered at the second working electrode due to the diffusion of
the H.sub.2O.sub.2 is aberrant and can cause improper data
processing in the sensor electronics. For example, if the second
electrode is configured to measure a substantially non-analyte
related signal (e.g., background) the sensor will record a higher
non-analyte related signal than is appropriate, possibly resulting
in the sensor reporting a lower analyte concentration than actually
is present in the host. This is discussed in greater detail
elsewhere herein.
In preferred embodiments, the non-conductive material is configured
to provide a diffusion barrier and structural support to the
sensor. Diffusion barriers are described elsewhere herein.
Non-conductive materials can be configured to support the sensor's
structure. In some, non-conductive materials with relatively more
or less rigidity can be selected. For example, if the electrodes
themselves are relatively flexible, it may be preferred to select a
relatively rigid non-conductive material, to make the sensor
stiffer (e.g., less flexible or bendable). In another example, if
the electrodes are sufficiently resilient or rigid, a very flexible
non-conductive material may be coated on the electrodes to bind the
electrodes together (e.g., keep the electrodes together and thereby
hold the sensor's shape).
Referring now to FIGS. 7C to 7J, the non-conductive material can be
coated on or wrapped around the grouped or bundled electrodes, to
prevent the electrodes from separating and also to prevent the
electrodes from directly touching each other. For example, with
reference to FIG. 7C, each electrode can be individually coated by
a first non-conductive material and then bundled together. Then the
bundle of individually insulated electrodes can be coated with a
second layer of the first non-conductive material or with a layer
or a second non-conductive material. In an embodiment of a sensor
having the structure shown in FIG. 7K, each electrode E1, E2 is
coated with a non-conductive material/insulator I, and then coated
with a second non-conductive material 703 (e.g., instead of a
biointerface membrane). Similarly, in FIG. 7L, the non-conductive
material I prevents electrodes E1 and E2 from making direct contact
with each other as well as giving the needle-like sensor its
overall dimensions and shape.
FIG. 7N illustrates one method of configuring a sensor having a
non-conductive material I that both provides electrical insulation
between the electrodes E1, E2, R and provides structural support to
the sensor. Namely, the electrodes are embedded in a non-conductive
polymer I, which is subsequently vulcanized (704=before shaping).
After vulcanization, the excess non-conductive polymer I is trimmed
away (e.g., cutting or scraping, etc.) to produce a sensor having
the final desired sensor shape 705=after shaping).
In some embodiments, a component of the sensor is configured to
provide both insulative properties and a diffusion barrier.
Diffusion barriers are discussed elsewhere herein. In one exemplary
embodiment, the working electrodes are separated by a
non-conductive material/insulator that is configured such that
electroactive species (e.g., H.sub.2O.sub.2) cannot diffuse around
it (e.g., from a first electrode to a second electrode). For
example, with reference to the embodiment shown in FIG. 7H, the
electrodes E1, E2 are placed in the groves carved into a cylinder
of non-conductive material I. The distance D from E1 to E2 (e.g.,
around I) is sufficiently great that H.sub.2O.sub.2 produced at E1
cannot diffuse to E2 and thereby cause an aberrant signal at
E2.
In some preferred embodiments, in addition to two working
electrodes and a non-conductive material/insulator, the sensor
includes at least a reference or a counter electrode. In preferred
embodiments, the reference and/or counter electrode, together with
the first and second working electrodes, integrally form at least a
portion of the sensor. In some embodiments, the reference and/or
counter electrode is located remote from the first and second
working electrodes. For example, in some embodiments, such as in
the case of a transcutaneous sensor, the reference and/or counter
electrodes can be located on the ex vivo portion of the sensor or
reside on the host's skin, such as a portion of an adhesive patch.
In other embodiments, such as in the case of an intravascular
sensor, the reference and/or counter electrode can be located on
the host's skin, within or on the fluid connector (e.g., coiled
within the ex vivo portion of the device and in contact with fluid
within the device, such as but not limited to saline) or on the
exterior of the ex vivo portion of the device. In preferred
embodiments, the surface area of the reference and/or counter
electrode is as least six times the surface area of at least one of
the first and second working electrodes. In a further embodiment,
the surface area of the reference and/or counter electrode is at
least ten times the surface area of at least one of the first and
second electrodes.
In preferred embodiments, the sensor is configured for implantation
into the host. The sensor can be configured for subcutaneous
implantation in the host's tissue (e.g., transcutaneous or wholly
implantable). Alternatively, the sensor can be configured for
indwelling in the host's blood stream (e.g., inserted through an
intravascular catheter or integrally formed on the exterior surface
of an intravascular catheter that is inserted into the host's blood
stream).
In some embodiments, the sensor is a glucose sensor that has a
first working electrode configured to generate a first signal
associated with glucose (e.g., the analyte) and non-glucose related
electroactive compounds (e.g., physiological baseline,
interferents, and non-constant noise) having a first oxidation
potential. For example, glucose has a first oxidation potential.
The interferents have an oxidation potential that is substantially
the same as the glucose oxidation potential (e.g., the first
oxidation potential). In a further embodiment, the glucose sensor
has a second working electrode that is configured to generate a
second signal associated with noise of the glucose sensor. The
noise of the glucose sensor is signal contribution due to
non-glucose related electroactive compounds (e.g., interferents)
that have an oxidation potential that substantially overlaps with
the first oxidation potential (e.g., the oxidation potential of
glucose, the analyte). In various embodiments, the non-glucose
related electroactive species include an interfering species,
non-reaction-related hydrogen peroxide, and/or other electroactive
species.
In preferred embodiments, the glucose sensor has electronics that
are operably connected to the first and second working electrodes
and are configured to provide the first and second signals to
generate glucose concentration data substantially without signal
contribution due to non-glucose-related noise. For example, the
sensor electronics analyze the signals from the first and second
working electrodes and calculate the portion of the first electrode
signal that is due to glucose concentration only. The portion of
the first electrode signal that is not due to the glucose
concentration can be considered to be background, such as but not
limited to noise.
In preferred embodiments, the glucose sensor has a non-conductive
material (e.g., insulative material) positioned between the first
and second working electrodes. The non-conductive material
substantially prevents cross talk between the first and second
working electrodes. For example, the electrical signal cannot pass
directly from a first insulated electrode to a second insulated
electrode. Accordingly, the second insulated electrode cannot
aberrantly record an electrical signal due to electrical signal
transfer from the first insulated electrode.
In preferred embodiments, the first and second working electrodes
and the non-conductive material integrally form at least a portion
of the sensor (e.g., a glucose sensor). The first and second
working electrodes integrally form a substantial portion of the
sensor configured for insertion in the host (e.g., the in vivo
portion of the sensor). In a further embodiment, the sensor (e.g.,
a glucose sensor) includes a reference electrode that, in addition
to the first and second working electrodes, integrally forms a
substantial portion of the sensor configured for insertion in the
host (e.g., the in vivo portion of the sensor). In yet a further
embodiment, the sensor (e.g., a glucose sensor) has an insulator
(e.g., non-conductive material), wherein the first and second
working electrodes and the insulator integrally form a substantial
portion of the sensor configured for insertion in the host (e.g.,
the in vivo portion of the sensor).
In preferred embodiments, the sensor (e.g., a glucose sensor)
includes a diffusion barrier configured to substantially block
diffusion of the analyte (e.g., glucose) or a co-analyte (e.g.,
H.sub.2O.sub.2) between the first and second working electrodes.
For example, as described with reference to FIG. 10, a diffusion
barrier D (e.g., spatial, physical and/or temporal) blocks
diffusion of a species (e.g., glucose and/or H.sub.2O.sub.2) from
the first working electrode E1 to the second working electrode E2.
In some embodiments, the diffusion barrier D is a physical
diffusion barrier, such as a structure between the working
electrodes that blocks glucose and H.sub.2O.sub.2 from diffusing
from the first working electrode E1 to the second working electrode
E2. In other embodiments, the diffusion barrier D is a spatial
diffusion barrier, such as a distance between the working
electrodes that blocks glucose and H.sub.2O.sub.2 from diffusing
from the first working electrode E1 to the second working electrode
E2. In still other embodiments, the diffusion barrier D is a
temporal diffusion barrier, such as a period of time between the
activity of the working electrodes such that if glucose or
H.sub.2O.sub.2 diffuses from the first working electrode E1 to the
second working electrode E2, the second working electrode E2 will
not substantially be influenced by the H.sub.2O.sub.2 from the
first working electrode E1.
With reference to FIG. 7H, if the diffusion barrier is spatial, a
distance D separates the working electrodes, such that the analyte
or co-analyte substantially cannot diffuse from a first electrode
E1 to a second electrode E2. In some embodiments, the diffusion
barrier is physical and configured from a material that
substantially prevents diffusion of the analyte or co-analyte there
through. Again referring to FIG. 7H, the insulator I and/or
reference electrode R is configured from a material that the
analyte or co-analyte cannot substantially pass through. For
example, H.sub.2O.sub.2 cannot substantially pass through a
silver/silver chloride reference electrode. In another example, a
parylene insulator can prevent H.sub.2O.sub.2 diffusion between
electrodes. In some embodiments, wherein the diffusion barrier is
temporal, the two electrodes are activated at separate,
non-overlapping times (e.g., pulsed). For example, the first
electrode E1 can be activated for a period of one second, followed
by activating the second electrode E2 three seconds later (e.g.,
after E1 has been inactivated) for a period of one second.
In additional embodiments, a component of the sensor is configured
to provide both a diffusional barrier and a structural support, as
discussed elsewhere herein. Namely, the diffusion barrier can be
configured of a material that is sufficiently rigid to support the
sensor's shape. In some embodiments, the diffusion barrier is an
electrode, such as but not limited to the reference and counter
electrodes (e.g., FIG. 7G to 7J and FIG. 8A). In other embodiments,
the diffusion barrier is an insulating coating (e.g., parylene) on
an electrode (e.g., FIG. 7K to 7L) or an insulating structure
separating the electrodes (e.g., FIG. 8A and FIG. 10).
One preferred embodiment provides a glucose sensor configured for
insertion into a host for measuring a glucose concentration in the
host. The sensor includes a first working electrode configured to
generate a first signal associated with glucose and non-glucose
related electroactive compounds having a first oxidation potential.
The sensor also includes a second working electrode configured to
generate a second signal associated with noise of the glucose
sensor comprising signal contribution due to non-glucose related
electroactive compounds that have an oxidation potential that
substantially overlaps with the first oxidation potential (e.g.,
the oxidation potential of H.sub.2O.sub.2). Additionally, the
glucose sensor includes a non-conductive material located between
the first and second working electrodes. Each of the first working
electrode, the second working electrode, and the non-conductive
material are configured to provide at least two functions selected
from the group consisting of: electrical conductance, insulative
properties, structural support, and diffusion barrier.
In some embodiments of the glucose sensor, each of the first
working electrode and the second working electrode are configured
to provide electrical conductance and structural support. For
example, the metal plated wire of electrodes conducts electricity
and helps maintain the sensor's shape. In a further embodiment, the
glucose sensor includes a reference electrode that is configured to
provide electrical conductance and structural support. For example,
the silver/silver chloride reference electrode is both electrically
conductive and supports the sensor's shape. In some embodiments of
the glucose sensor includes a reference electrode that is
configured to provide electrical conductance and a diffusion
barrier. For example, the silver/silver chloride reference
electrode can be configured as a large structure or protruding
structure, which separates the working electrodes by the distance D
(e.g., FIG. 7G). Distance "D" is sufficiently large that glucose
and/or H.sub.2O.sub.2 cannot substantially diffuse around the
reference electrode. Accordingly, H.sub.2O.sub.2 produced at a
first working electrode does not substantially contribute to signal
at a second working electrode. In some embodiments of the glucose
sensor includes a reference electrode that is configured to provide
a diffusion barrier and structural support. In some embodiments of
the glucose sensor, the non-conductive material is configured to
provide electrical insulative properties and structural support.
For example, non-conductive dielectric materials can insulate an
electrode and can be sufficiently rigid to stiffen the sensor. In
still other embodiments, the non-conductive material is configured
to provide electrical insulative properties and a diffusion
barrier. For example, a substantially rigid, non-conductive
dielectric can coat the electrodes and provide support, as shown in
FIG. 7L. In other embodiments, the non-conductive material is
configured to provide diffusion barrier and structural support. For
example, a dielectric material can protrude between the electrodes,
to act as a diffusion barrier and provide support to the sensor's
shape, as shown in FIG. 10.
Noise Reduction
In another aspect, the sensor is configured to reduce noise,
including non-constant non-analyte related noise with an
overlapping measuring potential with the analyte. A variety of
noise can occur when a sensor has been implanted in a host.
Generally, implantable sensors measure a signal (e.g., counts) that
generally comprises at least two components, the background signal
(e.g., background noise) and the analyte signal. The background
signal is composed substantially of signal contribution due to
factors other than glucose (e.g., interfering species,
non-reaction-related hydrogen peroxide, or other electroactive
species with an oxidation potential that overlaps with the analyte
or co-analyte). The analyte signal (e.g., glucose) is composed
substantially of signal contribution due to the analyte.
Consequently, because the signal includes these two components, a
calibration is performed in order to determine the analyte (e.g.,
glucose) concentration by solving for the equation y=mx+b, where
the value of b represents the background of the signal.
In some circumstances, the background is comprised of both constant
(e.g., baseline) and non-constant (e.g., noise) factors. Generally,
it is desirable to remove the background signal, to provide a more
accurate analyte concentration to the host or health care
professional.
The term "baseline" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a
substantially constant signal derived from certain electroactive
compounds found in the human body that are relatively constant
(e.g., baseline of the host's physiology, non-analyte related).
Therefore, baseline does not significantly adversely affect the
accuracy of the calibration of the analyte concentration (e.g.,
baseline can be relatively constantly eliminated using the equation
y=mx+b).
In contrast, "noise" as used herein is a broad term, and is to be
given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a
substantially intermittent signal caused by relatively non-constant
factors (e.g., the presence of intermittent noise-causing compounds
that have an oxidation potential that substantially overlaps the
oxidation potential of the analyte or co-analyte and arise due to
the host's ingestion, metabolism, wound healing, and other
mechanical, chemical and/or biochemical factors, also non-analyte
related). Noise can be difficult to remove from the sensor signal
by calibration using standard calibration equations (e.g., because
the background of the signal does not remain constant). Noise can
significantly adversely affect the accuracy of the calibration of
the analyte signal. Additionally noise, as described herein, can
occur in the signal of conventional sensors with electrode
configurations that are not particularly designed to measure noise
substantially equally at both active and inactive electrodes (e.g.,
wherein the electrodes are spaced and/or non symmetrical, noise may
not be equally measured and therefore not easily removed using
conventional dual electrode designs).
There are a variety of ways noise can be recognized and/or
analyzed. In preferred embodiments, the sensor data stream is
monitored, signal artifacts are detected, and data processing is
based at least in part on whether or not a signal artifact has been
detected, such as described in U.S. Publication No.
US-2005-0043598-A1 and co-pending U.S. application Ser. No.
11/503,367 filed Aug. 10, 2006 and entitled "ANALYTE SENSOR,"
herein incorporated by reference in its entirety.
Accordingly, if a sensor is designed such that the signal
contribution due to baseline and noise can be removed, then more
accurate analyte concentration data can be provided to the host or
a healthcare professional.
One embodiment provides an analyte sensor (e.g., glucose sensor)
configured for insertion into a host for measuring an analyte
(e.g., glucose) in the host. The sensor includes a first working
electrode disposed beneath an active enzymatic portion of a
membrane on the sensor; a second working electrode disposed beneath
an inactive- or non-enzymatic portion of the membrane on the
sensor; and electronics operably connected to the first and second
working electrode and configured to process the first and second
signals to generate an analyte (e.g., glucose) concentration
substantially without signal contribution due to non-glucose
related noise artifacts.
Referring now to FIG. 9B, in another embodiment, the sensor has a
first working electrode E1 and a second working electrode E2. The
sensor includes a membrane system (not shown) covering the
electrodes, as described elsewhere herein. A portion of the
membrane system on the first electrode contains active enzyme,
which is depicted schematically as oval 904a (e.g., active GOx). A
portion of the membrane system on the second electrode is
non-enzymatic or contains inactivated enzyme, which is depicted
schematically as oval 904b (e.g., heat- or chemically-inactivated
GOx or optionally no GOx). A portion of the sensor includes
electrical connectors 804. In some embodiments, the connectors 804
are located on an ex vivo portion of the sensor. Each electrode
(e.g., E1, E2, etc.) is connected to sensor electronics (not shown)
by a connector 804. Since the first electrode E1 includes active
GOx, it produces a first signal that is related to the
concentration of the analyte (in this case glucose) in the host as
well as other species that have an oxidation potential that
overlaps with the oxidation potential of the analyte or co-analyte
(e.g., non-glucose related noise artifacts, noise-causing
compounds, background). Since the second electrode E2 includes
inactive GOx, it produces a second signal that is not substantially
related to the analyte or co-analyte. Instead, the second signal is
substantially related to noise-causing compounds and other
background noise. The sensor electronics process the first and
second signals to generate an analyte concentration that is
substantially free of the non-analyte related noise artifacts.
Elimination or reduction of noise (e.g., non-constant background)
is attributed at least in part to the configuration of the
electrodes in the preferred embodiments, e.g., the locality of
first and second working electrode, the symmetrical or opposing
design of the first and second working electrodes, and/or the
overall sizing and configuration of the exposed electroactive
portions. Accordingly, the host is provided with improved analyte
concentration data, upon which he can make medical treatment
decisions (e.g., if he should eat, if he should take medication or
the amount of medication he should take). Advantageously, in the
case of glucose sensors, since the sensor can provide improved
quality of data, the host can be maintained under tighter glucose
control (e.g., about 80 mg/dl to about 120 mg/dl) with a reduced
risk of hypoglycemia and hypoglycemia's immediate complications
(e.g., coma or death). Additionally, the reduced risk of
hypoglycemia makes it possible to avoid the long-term complications
of hyperglycemia (e.g., kidney and heart disease, neuropathy, poor
healing, loss of eye sight) by consistently maintaining tight
glucose control (e.g., about 80 mg/dl to about 120 mg/dl).
In one embodiment, the sensor is configured to substantially
eliminate (e.g., subtract out) noise due to mechanical factors.
Mechanical factors include macro-motion of the sensor, micro-motion
of the sensor, pressure on the sensor, local tissue stress, and the
like. Since both working electrodes are constructed substantially
symmetrically and identically, and due to the sensor's small size,
the working electrodes are substantially equally affected by
mechanical factors impinging upon the sensor. For example, if a
build-up of noise-causing compounds occurs (e.g., due to the host
pressing upon and manipulating (e.g., fiddling with) the sensor,
for example) both working electrodes will measure the resulting
noise to substantially the same extend, while only one working
electrode (the first working electrode, for example) will also
measure signal due to the analyte concentration in the host's body.
The sensor then calculates the analyte signal (e.g., glucose-only
signal) by removing the noise that was measured by the second
working electrode from the total signal that was measured by the
first working electrode.
Non-analyte related noise can also be caused by biochemical and/or
chemical factors (e.g., compounds with electroactive acidic, amine
or sulfhydryl groups, urea, lactic acid, phosphates, citrates,
peroxides, amino acids (e.g., L-arginine), amino acid precursors or
break-down products, nitric oxide (NO), NO-donors, NO-precursors or
other electroactive species or metabolites produced during cell
metabolism and/or wound healing). As with noise due to mechanical
factors, noise due to biochemical/chemical factors will impinge
upon the two working electrodes of the preferred embodiments (e.g.,
with and without active GOx) about the same extent, because of the
sensor's small size and symmetrical configuration. Accordingly, the
sensor electronics can use these data to calculate the glucose-only
signal, as described elsewhere herein.
In one exemplary embodiment, the analyte sensor is a glucose sensor
that measures a first signal associated with both glucose and
non-glucose related electroactive compounds having a first
oxidation potential. For example, the oxidation potential of the
non-glucose related electroactive compounds substantially overlaps
with the oxidation potential of H.sub.2O.sub.2, which is produced
according to the reaction of glucose with GOx and subsequently
transfers electrons to the first working electrode (e.g., E1; FIG.
10). The glucose sensor also measures a second signal, which is
associated with background noise of the glucose sensor. The
background noise is composed of signal contribution due to
noise-causing compounds (e.g., interferents), non-reaction-related
hydrogen peroxide, or other electroactive species with an oxidation
potential that substantially overlaps with the oxidation potential
of H.sub.2O.sub.2 (the co-analyte). The first and second working
electrodes integrally form at least a portion of the sensor, such
as but not limited to the in vivo portion of the sensor, as
discussed elsewhere herein. Additionally, each of the first working
electrode, the second working electrode, and a non-conductive
material/insulator are configured provide at least two functions
(to the sensor), such as but not limited to electrical conductance,
insulative properties, structural support, and diffusion barrier
(described elsewhere herein). Furthermore, the sensor has a
diffusion barrier that substantially blocks diffusion of glucose or
H.sub.2O.sub.2 between the first and second working electrodes.
Diffusion Barrier
Another aspect of the sensor is a diffusion barrier, to prevent an
undesired species, such as H.sub.2O.sub.2 or the analyte, from
diffusing between active (with active enzyme) and inactive (without
active enzyme) electrodes. In various embodiments, the sensor
includes a diffusion barrier configured to be physical, spatial,
and/or temporal.
FIG. 10 is a schematic illustrating one embodiment of a sensor
(e.g., a portion of the in vivo portion of the sensor, such as but
not limited to the sensor electroactive surfaces) having one or
more components that act as a diffusion barrier (e.g., prevent
diffusion of electroactive species from one electrode to another).
The first working electrode E1 is coated with an enzyme layer 1000
comprising active enzyme. For example, in a glucose sensor, the
first working electrode E1 is coated with glucose oxidase enzyme
(GOx). A second working electrode E2 is separated from the first
working electrode E1 by a diffusion barrier D, such as but not
limited to a physical diffusion barrier (e.g., either a reference
electrode or a layer of non-conductive material/insulator). The
diffusion barrier can also be spatial or temporal, as discussed
elsewhere herein.
Glucose and oxygen diffuse into the enzyme layer 1000, where they
react with GOx, to produce gluconate and H.sub.2O.sub.2. At least a
portion of the H.sub.2O.sub.2 diffuses to the first working
electrode E1, where it is electrochemically oxidized to oxygen and
transfers two electrons (e.g., 2e.sup.-) to the first working
electrode E1, which results in a glucose signal that is recorded by
the sensor electronics (not shown). The remaining H.sub.2O.sub.2
can diffuse to other locations in the enzyme layer or out of the
enzyme layer (illustrated by the wavy arrows). Without a diffusion
barrier D, a portion of the H.sub.2O.sub.2 can diffuse to the
second working electrode E2, which results in an aberrant signal
that can be recorded by the sensor electronics as a non-glucose
related signal (e.g., background).
Preferred embodiments provide for a substantial diffusion barrier D
between the first and second working electrodes (E1, E2) such that
the H.sub.2O.sub.2 cannot substantially diffuse from the first
working electrode E1 to the second working electrode E2.
Accordingly, the possibility of an aberrant signal produced by
H.sub.2O.sub.2 from the first working electrode E1 (at the second
working electrode E2) is reduced or avoided.
In some alternative embodiments, the sensor is provided with a
spatial diffusion barrier between electrodes (e.g., the working
electrodes). For example, a spatial diffusion barrier can be
created by separating the first and second working electrodes by a
distance that is too great for the H.sub.2O.sub.2 to substantially
diffuse between the working electrodes. In some embodiments, the
spatial diffusion barrier is about 0.010 inches to about 0.120
inches. In other embodiments, the spatial diffusion barrier is
about 0.020 inches to about 0.050 inches. Still in other
embodiments, the spatial diffusion barrier is about 0.055 inches to
about 0.095 inches. A reference electrode R (e.g., a silver or
silver/silver chloride electrode) or a non-conductive material I
(e.g., a polymer structure or coating such as Parylene) can be
configured to act as a spatial diffusion barrier.
FIGS. 9A and 9B illustrate two exemplary embodiments of sensors
with spatial diffusion barriers. In each embodiment, the sensor has
two working electrodes E1 and E2. Each working electrode includes
an electroactive surface, represented schematically as windows 904a
and 904b, respectively. The sensor includes a membrane system (not
shown). Over one electroactive surface (e.g., 904a) the membrane
includes active enzyme (e.g., GOx). Over the second electroactive
surface (e.g., 904b) the membrane does not include active enzyme.
In some embodiments, the portion of the membrane covering the
second electroactive surface contains inactivated enzyme (e.g.,
heat- or chemically-inactivated GOx) while in other embodiments,
this portion of the membrane does not contain any enzyme (e.g.,
non-enzymatic). The electroactive surfaces 904a and 904b are
separated by a spatial diffusion barrier that is substantially wide
such that H.sub.2O.sub.2 produced at the first electroactive
surface 904a cannot substantially affect the second electroactive
surface 904b. In some alternative embodiments, the diffusion
barrier can be physical (e.g., a structure separating the
electroactive surfaces) or temporal (e.g., oscillating activity
between the electroactive surfaces).
In another embodiment, the sensor is an indwelling sensor, such as
configured for insertion into the host's circulatory system via a
vein or an artery. In some exemplary embodiments, an indwelling
sensor includes at least two working electrodes that are inserted
into the host's blood stream through a catheter. The sensor
includes at least a reference electrode that can be disposed either
with the working electrodes or remotely from the working
electrodes. The sensor includes a spatial, a physical, or a
temporal diffusion barrier. A spatial diffusion barrier can be
configured as described elsewhere herein, with reference to FIG. 7A
through FIG. 8A.
FIG. 9B provides one exemplary embodiment of an indwelling analyte
sensor, such as but not limited to an intravascular glucose sensor
to be used from a few hours to ten days or longer. Namely, the
sensor includes two working electrodes. One working electrode
detects the glucose-related signal (due to active GOx applied to
the electroactive surface) as well as non-glucose related signal.
The other working electrode detects only the non-glucose related
signal (because no active GOx is applied to its electroactive
surface). H.sub.2O.sub.2 is produced on the working electrode with
active GOx. If the H.sub.2O.sub.2 diffuses to the other working
electrode (the no GOx electrode) an aberrant signal will be
detected at this electrode, resulting in reduced sensor activity.
Accordingly, it is desirable to separate the electroactive surfaces
with a diffusion barrier, such as but not limited to a spatial
diffusion barrier. Indwelling sensors are described in more detail
in copending U.S. patent application Ser. Nos. 11/543,396,
11/543,490, and 11/543,404 [Pub. Nos. 2008-0119703 A1, 2008-0119704
A1, 2008-0119706 A1], entitled "Analyte sensor" and filed Oct. 4,
2006, herein incorporated in its entirety by reference.
To configure a spatial diffusion barrier between the working
electrodes, the location of the active enzyme (e.g., GOx) is
dependent upon the orientation of the sensor after insertion into
the host's artery or vein. For example, in an embodiment configured
for insertion upstream in the host's blood flow (e.g., against the
blood flow), active GOx would be applied to electroactive surface
904b and inactive GOX (or no GOx) would be applied to electroactive
surface 904a (e.g., upstream from 904b, relative to the direction
of blood flow). Due to this configuration, H.sub.2O.sub.2 produced
at electroactive surface 904b would be carrier down stream (e.g.,
away from electroactive surface 904a) and thus not affect electrode
E1.
Alternatively, the indwelling electrode can also be configured for
insertion of the sensor into the host's vein or artery in the
direction of the blood flow (e.g., pointing downstream). In this
configuration, referred to as a spatial diffusion barrier, or as a
flow path diffusion barrier, the active GOx can be advantageously
applied to electroactive surface 904a on the first working
electrode E1. The electroactive surface 904b on the second working
electrode E2 has no active GOx. Accordingly, H.sub.2O.sub.2
produced at electroactive surface 904a is carried away by the blood
flow, and has no substantial effect on the second working electrode
E2.
In another embodiment of an indwelling analyte sensor, the
reference electrode, which is generally configured of silver/silver
chloride, can extend beyond the working electrodes, to provide a
physical barrier around which the H.sub.2O.sub.2 generated at the
electrode comprising active GOx cannot pass the other working
electrode (that has active GOx). In some embodiments, the reference
electrode has a surface area that is at least six times larger than
the surface area of the working electrodes. In other embodiments, a
2-working electrode analyte sensor includes a counter electrode in
addition to the reference electrode. As is generally know in the
art, the inclusion of the counter electrode allows for a reduction
in the reference electrode's surface area, and thereby allows for
further miniaturization of the sensor (e.g., reduction in the
sensor's diameter and/or length, etc.).
FIG. 7H provides one exemplary embodiment of a spatial diffusion
barrier, wherein the reference electrode/non-conductive insulating
material R/I is sized and shaped such that H.sub.2O.sub.2 produced
at the first working electrode E1 (e.g., with enzyme) does not
substantially diffuse around the reference electrode/non-conductive
material R/I to the second working electrode E2 (e.g., without
enzyme). In another example, shown in FIG. 7J, the X-shaped the
reference electrode/non-conductive material R/I substantially
prevents diffusion of electroactive species from the first working
electrode E1 (e.g., with enzyme) to the second working electrode E2
(e.g., without enzyme). In another embodiment, such as the sensor
shown in FIG. 7A, the layer of non-conductive material I (between
the electrodes) is of a sufficient length that the H.sub.2O.sub.2
produced at one electrode cannot substantially diffuse to another
electrode. (e.g., from E1 to either E2 or E3; or from E2 to either
E1 or E3, etc.).
In some embodiments, a physical diffusion barrier is provided by a
physical structure, such as an electrode, insulator, and/or
membrane. For example, in the embodiments shown in FIGS. 7G to 7J,
the insulator (I) or reference electrode (R) act as a diffusion
barrier. As another example, the diffusion barrier can be a
bioprotective membrane (e.g., a membrane that substantially resists
or blocks the transport of a species (e.g., hydrogen peroxide),
such as CHRONOTHANE.RTM.-H (a polyetherurethaneurea based on
polytetramethylene glycol, polyethylene glycol, methylene
diisocyanate, and organic amines). As yet another example, the
diffusion barrier can be a resistance domain, as described in more
detail elsewhere herein; namely, a semipermeable membrane that
controls the flux of oxygen and an analyte (e.g., glucose) to the
underlying enzyme domain. Numerous other structures and membranes
can function as a physical diffusion barrier as is appreciated by
one skilled in the art.
In other embodiments, a temporal diffusion barrier is provided
(e.g., between the working electrodes). By temporal diffusion
barrier is meant a period of time that substantially prevents an
electroactive species (e.g., H.sub.2O.sub.2) from diffusing from a
first working electrode to a second working electrode. For example,
in some embodiments, the differential measurement can be obtained
by switching the bias potential of each electrode between the
measurement potential and a non-measurement potential. The bias
potentials can be held at each respective setting (e.g., high and
low bias settings) for as short as milliseconds to as long as
minutes or hours. Pulsed amperometric detection (PED) is one method
of quickly switching voltages, such as described in Bisenberger,
M.; Brauchle, C.; Hampp, N. A triple-step potential waveform at
enzyme multisensors with thick-film gold electrodes for detection
of glucose and sucrose. Sensors and Actuators 1995, B, 181-189,
which is incorporated herein by reference in its entirety. In some
embodiments, bias potential settings are held long enough to allow
equilibration.
One preferred embodiment provides a glucose sensor configured for
insertion into a host for measuring glucose in the host. The sensor
includes first and second working electrodes and an insulator
located between the first and second working electrodes. The first
working electrode is disposed beneath an active enzymatic portion
of a membrane on the sensor and the second working electrode is
disposed beneath an inactive- or non-enzymatic portion of the
membrane on the sensor. The sensor also includes a diffusion
barrier configured to substantially block diffusion of glucose or
hydrogen peroxide between the first and second working
electrodes.
In a further embodiment, the glucose sensor includes a reference
electrode configured integrally with the first and second working
electrodes. In some embodiments, the reference electrode can be
located remotely from the sensor, as described elsewhere herein. In
some embodiments, the surface area of the reference electrode is at
least six times the surface area of the working electrodes. In some
embodiments, the sensor includes a counter electrode that is
integral to the sensor or is located remote from the sensor, as
described elsewhere herein.
In a further embodiment, the glucose sensor detects a first signal
associated with glucose and non-glucose related electroactive
compounds having a first oxidation potential (e.g., the oxidation
potential of H.sub.2O.sub.2). In some embodiments, the glucose
sensor also detects a second signal is associated with background
noise of the glucose sensor comprising signal contribution due to
interfering species, non-reaction-related hydrogen peroxide, or
other electroactive species with an oxidation potential that
substantially overlaps with the oxidation potential of hydrogen
peroxide; the first and second working electrodes integrally form
at least a portion of the sensor; and each of the first working
electrode, the second working electrode and the non-conductive
material/insulator are configured provide at least two functions
such as but not limited to electrical conductance, insulation,
structural support, and a diffusion barrier.
In further embodiments, the glucose sensor includes electronics
operably connected to the first and second working electrodes. The
electronics are configured to calculate at least one analyte sensor
data point using the first and second signals described above. In
still another further embodiment, the electronics are operably
connected to the first and second working electrode and are
configured to process the first and second signals to generate a
glucose concentration substantially without signal contribution due
to non-glucose noise artifacts.
Membrane Configurations
FIGS. 3A to 3B are cross-sectional exploded schematic views of the
sensing region of a glucose sensor 10, which show architectures of
the membrane system 22 disposed over electroactive surfaces of
glucose sensors in some embodiments. In the illustrated embodiments
of FIGS. 3A and 3B, the membrane system 22 is positioned at least
over the glucose-measuring working electrode 16 and the optional
auxiliary working electrode 18; however the membrane system may be
positioned over the reference and/or counter electrodes 20, 22 in
some embodiments.
Reference is now made to FIG. 3A, which is a cross-sectional
exploded schematic view of the sensing region in one embodiment
wherein an active enzyme 32 of the enzyme domain is positioned only
over the glucose-measuring working electrode 16. In this
embodiment, the membrane system is formed such that the glucose
oxidase 32 only exists above the glucose-measuring working
electrode 16. In one embodiment, during the preparation of the
membrane system 22, the enzyme domain coating solution can be
applied as a circular region similar to the diameter of the
glucose-measuring working electrode 16. This fabrication can be
accomplished in a variety of ways such as screen-printing or pad
printing. Preferably, the enzyme domain is pad printed during the
enzyme domain fabrication with equipment as available from Pad
Print Machinery of Vermont (Manchester, Vt.). This embodiment
provides the active enzyme 32 above the glucose-measuring working
electrode 16 only, so that the glucose-measuring working electrode
16 (and not the auxiliary working electrode 18) measures glucose
concentration. Additionally, this embodiment provides an added
advantage of eliminating the consumption of O.sub.2 above the
counter electrode (if applicable) by the oxidation of glucose with
glucose oxidase.
FIG. 3B is a cross-sectional exploded schematic view of a sensing
region of the preferred embodiments, and wherein the portion of the
active enzyme within the membrane system 22 positioned over the
auxiliary working electrode 18 has been deactivated 34. In one
alternative embodiment, the enzyme of the membrane system 22 may be
deactivated 34 everywhere except for the area covering the
glucose-measuring working electrode 16 or may be selectively
deactivated only over certain areas (for example, auxiliary working
electrode 18, counter electrode 22, and/or reference electrode 20)
by irradiation, heat, proteolysis, solvent, or the like. In such a
case, a mask (for example, such as those used for photolithography)
can be placed above the membrane that covers the glucose-measuring
working electrode 16. In this way, exposure of the masked membrane
to ultraviolet light deactivates the glucose oxidase in all regions
except that covered by the mask.
In some alternative embodiments, the membrane system is disposed on
the surface of the electrode(s) using known deposition techniques.
The electrode-exposed surfaces can be inset within the sensor body,
planar with the sensor body, or extending from the sensor body.
Although some examples of membrane systems have been provided
above, the concepts described herein can be applied to numerous
known architectures not described herein.
Sensor Electronics
In some embodiments, the sensing region may include reference
and/or electrodes associated with the glucose-measuring working
electrode and separate reference and/or counter electrodes
associated with the optional auxiliary working electrode(s). In yet
another embodiment, the sensing region may include a
glucose-measuring working electrode, an auxiliary working
electrode, two counter electrodes (one for each working electrode),
and one shared reference electrode. In yet another embodiment, the
sensing region may include a glucose-measuring working electrode,
an auxiliary working electrode, two reference electrodes, and one
shared counter electrode. However, a variety of electrode materials
and configurations can be used with the implantable analyte sensor
of the preferred embodiments.
In some alternative embodiments, the working electrodes are
interdigitated. In some alternative embodiments, the working
electrodes each comprise multiple exposed electrode surfaces; one
advantage of these architectures is to distribute the measurements
across a greater surface area to overcome localized problems that
may occur in vivo, for example, with the host's immune response at
the biointerface. Preferably, the glucose-measuring and auxiliary
working electrodes are provided within the same local environment,
such as described in more detail elsewhere herein.
FIG. 4 is a block diagram that illustrates the continuous glucose
sensor electronics in one embodiment. In this embodiment, a first
potentiostat 36 is provided that is operatively associated with the
glucose-measuring working electrode 16. The first potentiostat 36
measures a current value at the glucose-measuring working electrode
and preferably includes a resistor (not shown) that translates the
current into voltage. An optional second potentiostat 37 is
provided that is operatively associated with the optional auxiliary
working electrode 18. The second potentiostat 37 measures a current
value at the auxiliary working electrode 18 and preferably includes
a resistor (not shown) that translates the current into voltage. It
is noted that in some embodiments, the optional auxiliary electrode
can be configured to share the first potentiostat with the
glucose-measuring working electrode. An A/D converter 38 digitizes
the analog signals from the potentiostats 36, 37 into counts for
processing. Accordingly, resulting raw data streams (in counts) can
be provided that are directly related to the current measured by
each of the potentiostats 36 and 37.
A microprocessor 40, also referred to as the processor module, is
the central control unit that houses EEPROM 42 and SRAM 44, and
controls the processing of the sensor electronics. It is noted that
certain alternative embodiments can utilize a computer system other
than a microprocessor to process data as described herein. In other
alternative embodiments, an application-specific integrated circuit
(ASIC) can be used for some or all the sensor's central processing.
The EEPROM 42 provides semi-permanent storage of data, for example,
storing data such as sensor identifier (ID) and programming to
process data streams (for example, such as described in U.S.
Publication No. US-2005-0027463-A1, which is incorporated by
reference herein in its entirety. The SRAM 44 can be used for the
system's cache memory, for example for temporarily storing recent
sensor data. In some alternative embodiments, memory storage
components comparable to EEPROM and SRAM may be used instead of or
in addition to the preferred hardware, such as dynamic RAM,
non-static RAM, rewritable ROMs, flash memory, or the like.
A battery 46 is operably connected to the microprocessor 40 and
provides the necessary power for the sensor 10a. In one embodiment,
the battery is a Lithium Manganese Dioxide battery, however any
appropriately sized and powered battery can be used (for example,
AAA, Nickel-cadmium, Zinc-carbon, Alkaline, Lithium, Nickel-metal
hydride, Lithium-ion, Zinc-air, Zinc-mercury oxide, Silver-zinc,
and/or hermetically-sealed). In some embodiments the battery is
rechargeable. In some embodiments, a plurality of batteries can be
used to power the system. In some embodiments, one or more
capacitors can be used to power the system. A Quartz Crystal 48 may
be operably connected to the microprocessor 40 to maintain system
time for the computer system as a whole.
An RF Transceiver 50 may be operably connected to the
microprocessor 40 to transmit the sensor data from the sensor 10 to
a receiver (see FIGS. 4 and 5) within a wireless transmission 52
via antenna 54. Although an RF transceiver is shown here, some
other embodiments can include a wired rather than wireless
connection to the receiver. In yet other embodiments, the receiver
can be transcutaneously powered via an inductive coupling, for
example. A second quartz crystal 56 can provide the system time for
synchronizing the data transmissions from the RF transceiver. It is
noted that the transceiver 50 can be substituted with a transmitter
in other embodiments. In some alternative embodiments other
mechanisms such as optical, infrared radiation (IR), ultrasonic, or
the like may be used to transmit and/or receive data.
Receiver
FIG. 5 is a schematic drawing of a receiver for the continuous
glucose sensor in one embodiment. The receiver 58 comprises systems
necessary to receive, process, and display sensor data from the
analyte sensor, such as described in more detail elsewhere herein.
Particularly, the receiver 58 may be a pager-sized device, for
example, and house a user interface that has a plurality of buttons
and/or keypad and a liquid crystal display (LCD) screen, and which
may include a backlight. In some embodiments the user interface may
also include a speaker, and a vibrator such as described with
reference to FIG. 6.
FIG. 6 is a block diagram of the receiver electronics in one
embodiment. In some embodiments, the receiver comprises a
configuration such as described with reference to FIG. 5, above.
However, the receiver may comprise any reasonable configuration,
including a desktop computer, laptop computer, a personal digital
assistant (PDA), a server (local or remote to the receiver), or the
like. In some embodiments, a receiver may be adapted to connect
(via wired or wireless connection) to a desktop computer, laptop
computer, a PDA, a server (local or remote to the receiver), or the
like in order to download data from the receiver. In some
alternative embodiments, the receiver may be housed within or
directly connected to the sensor in a manner that allows sensor and
receiver electronics to work directly together and/or share data
processing resources. Accordingly, the receiver, including its
electronics, may be generally described as a "computer system."
A quartz crystal 60 may be operably connected to an RF transceiver
62 that together function to receive and synchronize data streams
via an antenna 64 (for example, transmission 52 from the RF
transceiver 50 shown in FIG. 4). Once received, a microprocessor 66
can process the signals, such as described below.
The microprocessor 66, also referred to as the processor module, is
the central control unit that provides the processing, such as
storing data, calibrating sensor data, downloading data,
controlling the user interface by providing prompts, messages,
warnings and alarms, or the like. The EEPROM 68 may be operably
connected to the microprocessor 66 and provides semi-permanent
storage of data, storing data such as receiver ID and programming
to process data streams (for example, programming for performing
calibration and other algorithms described elsewhere herein). SRAM
70 may be used for the system's cache memory and is helpful in data
processing. For example, the SRAM stores information from the
continuous glucose sensor for later recall by the patient or a
doctor; a patient or doctor can transcribe the stored information
at a later time to determine compliance with the medical regimen or
a comparison of glucose concentration to medication administration
(for example, this can be accomplished by downloading the
information through the pc corn port 76). In addition, the SRAM 70
can also store updated program instructions and/or patient specific
information. In some alternative embodiments, memory storage
components comparable to EEPROM and SRAM can be used instead of or
in addition to the preferred hardware, such as dynamic RAM,
non-static RAM, rewritable ROMs, flash memory, or the like.
A battery 72 may be operably connected to the microprocessor 66 and
provides power for the receiver. In one embodiment, the battery is
a standard AAA alkaline battery, however any appropriately sized
and powered battery can be used. In some embodiments, a plurality
of batteries can be used to power the system. In some embodiments,
a power port (not shown) is provided permit recharging of
rechargeable batteries. A quartz crystal 84 may be operably
connected to the microprocessor 66 and maintains system time for
the system as a whole.
A PC communication (com) port 76 can be provided to enable
communication with systems, for example, a serial communications
port, allows for communicating with another computer system (for
example, PC, PDA, server, or the like). In one exemplary
embodiment, the receiver is able to download historical data to a
physician's PC for retrospective analysis by the physician. The PC
communication port 76 can also be used to interface with other
medical devices, for example pacemakers, implanted analyte sensor
patches, infusion devices, telemetry devices, or the like.
A user interface 78 comprises a keypad 80, speaker 82, vibrator 84,
backlight 86, liquid crystal display (LCD) 88, and one or more
buttons 90. The components that comprise the user interface 78
provide controls to interact with the user. The keypad 80 can
allow, for example, input of user information about
himself/herself, such as mealtime, exercise, insulin
administration, and reference glucose values. The speaker 82 can
provide, for example, audible signals or alerts for conditions such
as present and/or predicted hyper- and hypoglycemic conditions. The
vibrator 84 can provide, for example, tactile signals or alerts for
reasons such as described with reference to the speaker, above. The
backlight 94 can be provided, for example, to aid the user in
reading the LCD in low light conditions. The LCD 88 can be
provided, for example, to provide the user with visual data output.
In some embodiments, the LCD is a touch-activated screen. The
buttons 90 can provide for toggle, menu selection, option
selection, mode selection, and reset, for example. In some
alternative embodiments, a microphone can be provided to allow for
voice-activated control.
The user interface 78, which is operably connected to the
microprocessor 70, serves to provide data input and output for the
continuous analyte sensor. In some embodiments, prompts can be
displayed to inform the user about necessary maintenance
procedures, such as "Calibrate Sensor" or "Replace Battery." In
some embodiments, prompts or messages can be displayed on the user
interface to convey information to the user, such as malfunction,
outlier values, missed data transmissions, or the like.
Additionally, prompts can be displayed to guide the user through
calibration of the continuous glucose sensor, for example when to
obtain a reference glucose value.
Keypad, buttons, touch-screen, and microphone are all examples of
mechanisms by which a user can input data directly into the
receiver. A server, personal computer, personal digital assistant,
insulin pump, and insulin pen are examples of external devices that
can be connected to the receiver via PC com port 76 to provide
useful information to the receiver. Other devices internal or
external to the sensor that measure other aspects of a patient's
body (for example, temperature sensor, accelerometer, heart rate
monitor, oxygen monitor, or the like) can be used to provide input
helpful in data processing. In one embodiment, the user interface
can prompt the patient to select an activity most closely related
to their present activity, which can be helpful in linking to an
individual's physiological patterns, or other data processing. In
another embodiment, a temperature sensor and/or heart rate monitor
can provide information helpful in linking activity, metabolism,
and glucose excursions of an individual. While a few examples of
data input have been provided here, a variety of information can be
input and can be helpful in data processing as will be understood
by one skilled in the art.
Calibration Systems and Methods
As described above in the Overview Section, continuous analyte
sensors define a relationship between sensor-generated measurements
and a reference measurement that is meaningful to a user (for
example, blood glucose in mg/dL). This defined relationship must be
monitored to ensure that the continuous analyte sensor maintains a
substantially accurate calibration and thereby continually provides
meaningful values to a user. Unfortunately, both sensitivity m and
baseline b of the calibration are subject to changes that occur in
vivo over time (for example, hours to months), requiring updates to
the calibration. Generally, any physical property that influences
diffusion or transport of molecules through the membrane can alter
the sensitivity (and/or baseline) of the calibration. Physical
properties that can alter the transport of molecules include, but
are not limited to, blockage of surface area due to foreign body
giant cells and other barrier cells at the biointerface, distance
of capillaries from the membrane, foreign body response/capsule,
disease, tissue ingrowth, thickness of membrane system, or the
like.
In one example of a change in transport of molecules, an
implantable glucose sensor is implanted in the subcutaneous space
of a human, which is at least partially covered with a biointerface
membrane, such as described in U.S. Publication No.
US-2005-0112169-A1, which is incorporated by reference herein in
its entirety. Although the body's natural response to a foreign
object is to encapsulate the sensor, the architecture of this
biointerface membrane encourages tissue ingrowth and
neo-vascularization over time, providing transport of solutes (for
example, glucose and oxygen) close to the membrane that covers the
electrodes. While not wishing to be bound by theory, it is believed
that ingrowth of vascularized tissue matures (changes) over time,
beginning with a short period of high solute transport during the
first few days after implantation, continuing through a time period
of significant tissue ingrowth a few days to a week or more after
implantation during which low solute transport to the membrane has
been observed, and into a mature state of vascularized tissue
during which the bed of vascularized tissue provides moderate to
high solute transport, which can last for months and even longer
after implantation. In some embodiments, this maturation process
accounts for a substantial portion of the change in sensitivity
and/or baseline of the calibration over time due to changes in
solute transport to the membrane.
Accordingly, in one aspect of the preferred embodiments, systems
and methods are provided for measuring changes in sensitivity, also
referred to as changes in solute transport or biointerface changes,
of an analyte sensor 10 implanted in a host over a time period.
Preferably, the sensitivity measurement is a signal obtained by
measuring a constant analyte other than the analyte being measured
by the analyte sensor. For example, in a glucose sensor, a
non-glucose constant analyte is measured, wherein the signal is
measured beneath the membrane system 22 on the glucose sensor 10.
While not wishing to be bound by theory, it is believed that by
monitoring the sensitivity over a time period, a change associated
with solute transport through the membrane system 22 can be
measured and used as an indication of a sensitivity change in the
analyte measurement. In other words, a biointerface monitor is
provided, which is capable of monitoring changes in the
biointerface surrounding an implantable device, thereby enabling
the measurement of sensitivity changes of an analyte sensor over
time.
In some embodiments, the analyte sensor 10 is provided with an
auxiliary electrode 18 configured as a transport-measuring
electrode disposed beneath the membrane system 22. The
transport-measuring electrode can be configured to measure any of a
number of substantially constant analytes or factors, such that a
change measured by the transport-measuring electrode can be used to
indicate a change in solute (for example, glucose) transport to the
membrane system 22. Some examples of substantially constant
analytes or factors that can be measured include, but are not
limited to, oxygen, carboxylic acids (such as urea), amino acids,
hydrogen, pH, chloride, baseline, or the like. Thus, the
transport-measuring electrode provides an independent measure of
changes in solute transport to the membrane, and thus sensitivity
changes over time.
In some embodiments, the transport-measuring electrode measures
analytes similar to the analyte being measured by the analyte
sensor. For example, in some embodiments of a glucose sensor, water
soluble analytes are believed to better represent the changes in
sensitivity to glucose over time than non-water soluble analytes
(due to the water-solubility of glucose), however relevant
information may be ascertained from a variety of molecules.
Although some specific examples are described herein, one skilled
in the art appreciates a variety of implementations of sensitivity
measurements that can be used as to qualify or quantify solute
transport through the biointerface of the analyte sensor.
In one embodiment of a glucose sensor, the transport-measuring
electrode is configured to measure urea, which is a water-soluble
constant analyte that is known to react directly or indirectly at a
hydrogen peroxide sensing electrode (similar to the working
electrode of the glucose sensor example described in more detail
above). In one exemplary implementation wherein urea is directly
measured by the transport-measuring electrode, the glucose sensor
comprises a membrane system as described in more detail above,
however, does not include an active interference domain or active
enzyme directly above the transport-measuring electrode, thereby
allowing the urea to pass through the membrane system to the
electroactive surface for measurement thereon. In one alternative
exemplary implementation wherein urea is indirectly measured by the
transport-measuring electrode, the glucose sensor comprises a
membrane system as described in more detail above, and further
includes an active uricase oxidase domain located directly above
the transport-measuring electrode, thereby allowing the urea to
react at the enzyme and produce hydrogen peroxide, which can be
measured at the electroactive surface thereon.
In some embodiments, the change in sensitivity is measured by
measuring a change in oxygen concentration, which can be used to
provide an independent measurement of the maturation of the
biointerface, and to indicate when recalibration of the system may
be advantageous. In one alternative embodiment, oxygen is measured
using pulsed amperometric detection on the glucose-measuring
working electrode 16 (eliminating the need for a separate auxiliary
electrode). In another embodiment, the auxiliary electrode is
configured as an oxygen-measuring electrode. In another embodiment,
an oxygen sensor (not shown) is added to the glucose sensor, as is
appreciated by one skilled in the art, eliminating the need for an
auxiliary electrode.
In some embodiments, a stability module is provided; wherein the
sensitivity measurement changes can be quantified such that a
co-analyte concentration threshold is determined. A co-analyte
threshold is generally defined as a minimum amount of co-analyte
required to fully react with the analyte in an enzyme-based analyte
sensor in a non-limiting manner. The minimum co-analyte threshold
is preferably expressed as a ratio (for example, a
glucose-to-oxygen ratio) that defines a concentration of co-analyte
required based on a concentration of analyte available to ensure
that the enzyme reaction is limited only by the analyte. While not
wishing to be bound by theory, it is believed that by determining a
stability of the analyte sensor based on a co-analyte threshold,
the processor module can be configured to compensate for
instabilities in the glucose sensor accordingly, for example by
filtering the unstable data, suspending calibration or display, or
the like.
In one such embodiment, a data stream from an analyte signal is
monitored and a co-analyte threshold set, whereby the co-analyte
threshold is determined based on a signal-to-noise ratio exceeding
a predetermined threshold. In one embodiment, the signal-to-noise
threshold is based on measurements of variability and the sensor
signal over a time period, however one skilled in the art
appreciates the variety of systems and methods available for
measuring signal-to-noise ratios. Accordingly, the stability module
can be configured to set determine the stability of the analyte
sensor based on the co-analyte threshold, or the like.
In some embodiments, the stability module is configured to prohibit
calibration of the sensor responsive to the stability (or
instability) of the sensor. In some embodiments, the stability
module can be configured to trigger filtering of the glucose signal
responsive to a stability (or instability) of the sensor.
In some embodiments, sensitivity changes can be used to trigger a
request for one or more new reference glucose values from the host,
which can be used to recalibrate the sensor. In some embodiments,
the sensor is re-calibrated responsive to a sensitivity change
exceeding a preselected threshold value. In some embodiments, the
sensor is calibrated repeatedly at a frequency responsive to the
measured sensitivity change. Using these techniques, patient
inconvenience can be minimized because reference glucose values are
generally only requested when timely and appropriate (namely, when
a sensitivity or baseline shift is diagnosed).
In some alternative embodiments, sensitivity changes can be used to
update calibration. For example, the measured change in transport
can be used to update the sensitivity m in the calibration
equation. While not wishing to be bound by theory, it is believed
that in some embodiments, the sensitivity m of the calibration of
the glucose sensor is substantially proportional to the change in
solute transport measured by the transport-measuring electrode.
It should be appreciated by one skilled in the art that in some
embodiments, the implementation of sensitivity measurements of the
preferred embodiments typically necessitate an addition to, or
modification of, the existing electronics (for example,
potentiostat configuration or settings) of the glucose sensor
and/or receiver.
In some embodiments, the signal from the oxygen measuring electrode
may be digitally low-pass filtered (for example, with a passband of
0-10.sup.-5 Hz, dc-24 hour cycle lengths) to remove transient
fluctuations in oxygen, due to local ischemia, postural effects,
periods of apnea, or the like. Since oxygen delivery to tissues is
held in tight homeostatic control, this filtered oxygen signal
should oscillate about a relatively constant. In the interstitial
fluid, it is thought that the levels are about equivalent with
venous blood (40 mmHg). Once implanted, changes in the mean of the
oxygen signal (for example, >5%) may be indicative of change in
transport through the biointerface (change in sensor sensitivity
and/or baseline due to changes in solute transport) and the need
for system recalibration.
The oxygen signal may also be used in its unfiltered or a minimally
filtered form to detect or predict oxygen deprivation-induced
artifact in the glucose signal, and to control display of data to
the user, or the method of smoothing, digital filtering, or
otherwise replacement of glucose signal artifact. In some
embodiments, the oxygen sensor may be implemented in conjunction
with any signal artifact detection or prediction that may be
performed on the counter electrode or working electrode voltage
signals of the electrode system. U.S. Publication No.
US-2005-0043598-A1, which is incorporated by reference in its
entirety herein, describes some methods of signal artifact
detection and replacement that may be useful such as described
herein.
Preferably, the transport-measuring electrode is located within the
same local environment as the electrode system associated with the
measurement of glucose, such that the transport properties at the
transport-measuring electrode are substantially similar to the
transport properties at the glucose-measuring electrode.
In a second aspect the preferred embodiments, systems and methods
are provided for measuring changes baseline, namely non-glucose
related electroactive compounds in the host. Preferably the
auxiliary working electrode is configured to measure the baseline
of the analyte sensor over time. In some embodiments, the
glucose-measuring working electrode 16 is a hydrogen peroxide
sensor coupled to a membrane system 22 containing an active enzyme
32 located above the electrode (such as described in more detail
with reference to FIGS. 1 to 4, above). In some embodiments, the
auxiliary working electrode 18 is another hydrogen peroxide sensor
that is configured similar to the glucose-measuring working
electrode however a portion 34 of the membrane system 22 above the
base-measuring electrode does not have active enzyme therein, such
as described in more detail with reference to FIGS. 3A and 3B. The
auxiliary working electrode 18 provides a signal substantially
comprising the baseline signal, b, which can be (for example,
electronically or digitally) subtracted from the glucose signal
obtained from the glucose-measuring working electrode to obtain the
signal contribution due to glucose only according to the following
equation: Signal.sub.glucose only=Signal.sub.glucose-measuring
working electrode-Signal.sub.baseline-measuring working
electrode
In some embodiments, electronic subtraction of the baseline signal
from the glucose signal can be performed in the hardware of the
sensor, for example using a differential amplifier. In some
alternative embodiments, digital subtraction of the baseline signal
from the glucose signal can be performed in the software or
hardware of the sensor or an associated receiver, for example in
the microprocessor.
One aspect the preferred embodiments provides for a simplified
calibration technique, wherein the variability of the baseline has
been eliminated (namely, subtracted). Namely, calibration of the
resultant differential signal (Signal.sub.glucose only) can be
performed with a single matched data pair by solving the following
equation: y=mx
While not wishing to be bound by theory, it is believed that by
calibrating using this simplified technique, the sensor is made
less dependent on the range of values of the matched data pairs,
which can be sensitive to human error in manual blood glucose
measurements, for example. Additionally, by subtracting the
baseline at the sensor (rather than solving for the baseline b as
in conventional calibration schemes), accuracy of the sensor may
increase by altering control of this variable (baseline b) from the
user to the sensor. It is additionally believed that variability
introduced by sensor calibration may be reduced.
In some embodiments, the glucose-measuring working electrode 16 is
a hydrogen peroxide sensor coupled to a membrane system 22
containing an active enzyme 32 located above the electrode, such as
described in more detail above; however the baseline signal is not
subtracted from the glucose signal for calibration of the sensor.
Rather, multiple matched data pairs are obtained in order to
calibrate the sensor (for example using y=mx+b) in a conventional
manner, and the auxiliary working electrode 18 is used as an
indicator of baseline shifts in the sensor signal. Namely, the
auxiliary working electrode 18 is monitored for changes above a
certain threshold. When a significant change is detected, the
system can trigger a request (for example, from the patient or
caregiver) for a new reference glucose value (for example, SMBG),
which can be used to recalibrate the sensor. By using the auxiliary
working electrode signal as an indicator of baseline shifts,
recalibration requiring user interaction (namely, new reference
glucose values) can be minimized due to timeliness and
appropriateness of the requests. In some embodiments, the sensor is
re-calibrated responsive to a baseline shifts exceeding a
preselected threshold value. In some embodiments, the sensor is
calibrated repeatedly at a frequency responsive to the
rate-of-change of the baseline.
In yet another alternative embodiment, the electrode system of the
preferred embodiments is employed as described above, including
determining the differential signal of glucose less baseline
current in order to calibrate using the simplified equation (y=mx),
and the auxiliary working electrode 18 is further utilized as an
indicator of baseline shifts in the sensor signal. While not
wishing to be bound by theory, it is believed that shifts in
baseline may also correlate and/or be related to changes in the
sensitivity m of the glucose signal. Consequently, a shift in
baseline may be indicative of a change in sensitivity m. Therefore,
the auxiliary working electrode 18 is monitored for changes above a
certain threshold. When a significant change is detected, the
system can trigger a request (for example, from the patient or
caregiver) for a new reference glucose value (for example, SMBG),
which can be used to recalibrate the sensor. By using the auxiliary
signal as an indicator of possible sensitivity changes,
recalibration requiring user interaction (new reference glucose
values) can be minimized due to timeliness and appropriateness of
the requests.
It is noted that infrequent new matching data pairs may be useful
over time to recalibrate the sensor because the sensitivity m of
the sensor may change over time (for example, due to maturation of
the biointerface that may increase or decrease the glucose and/or
oxygen availability to the sensor). However, the baseline shifts
that have conventionally required numerous and/or regular blood
glucose reference measurements for updating calibration (for
example, due to interfering species, metabolism changes, or the
like) can be consistently and accurately eliminated using the
systems and methods of the preferred embodiments, allowing reduced
interaction from the patient (for example, requesting less frequent
reference glucose values such as daily or even as infrequently as
monthly).
An additional advantage of the sensor of the preferred embodiments
includes providing a method of eliminating signal effects of
interfering species, which have conventionally been problematic in
electrochemical glucose sensors. Namely, electrochemical sensors
are subject to electrochemical reaction not only with the hydrogen
peroxide (or other analyte to be measured), but additionally may
react with other electroactive species that are not intentionally
being measured (for example, interfering species), which cause an
increase in signal strength due to this interference. In other
words, interfering species are compounds with an oxidation
potential that overlap with the analyte being measured. Interfering
species such as acetaminophen, ascorbate, and urate, are notorious
in the art of glucose sensors for producing inaccurate signal
strength when they are not properly controlled. Some glucose
sensors utilize a membrane system that blocks at least some
interfering species, such as ascorbate and urate. Unfortunately, it
is difficult to find membranes that are satisfactory or reliable in
use, especially in vivo, which effectively block all interferants
and/or interfering species (for example, see U.S. Pat. No.
4,776,944, U.S. Pat. No. 5,356,786, U.S. Pat. No. 5,593,852, U.S.
Pat. No. 5,776,324 B1, and U.S. Pat. No. 6,356,776).
The preferred embodiments are particularly advantageous in their
inherent ability to eliminate the erroneous transient and
non-transient signal effects normally caused by interfering
species. For example, if an interferant such as acetaminophen is
ingested by a host implanted with a conventional implantable
electrochemical glucose sensor (namely, one without means for
eliminating acetaminophen), a transient non-glucose related
increase in signal output would occur. However, by utilizing the
electrode system of the preferred embodiments, both working
electrodes respond with substantially equivalent increased current
generation due to oxidation of the acetaminophen, which would be
eliminated by subtraction of the auxiliary electrode signal from
the glucose-measuring electrode signal.
In summary, the system and methods of the preferred embodiments
simplify the computation processes of calibration, decreases the
susceptibility introduced by user error in calibration, and
eliminates the effects of interfering species. Accordingly, the
sensor requires less interaction by the patient (for example, less
frequent calibration), increases patient convenience (for example,
few reference glucose values), and improves accuracy (via simple
and reliable calibration).
In another aspect of the preferred embodiments, the analyte sensor
is configured to measure any combination of changes in baseline
and/or in sensitivity, simultaneously and/or iteratively, using any
of the above-described systems and methods. While not wishing to be
bound by theory, the preferred embodiments provide for improved
calibration of the sensor, increased patient convenience through
less frequent patient interaction with the sensor, less dependence
on the values/range of the paired measurements, less sensitivity to
error normally found in manual reference glucose measurements,
adaptation to the maturation of the biointerface over time,
elimination of erroneous signal due to non-constant analyte-related
signal so interfering species, and/or self-diagnosis of the
calibration for more intelligent recalibration of the sensor.
EXAMPLES
Example 1
Dual--Electrode Sensor with Coiled Reference Electrode
Dual-electrode sensors (having a configuration similar to the
embodiment shown in FIG. 9B) were constructed from two platinum
wires, each coated with non-conductive material/insulator. Exposed
electroactive windows were cut into the wires by removing a portion
thereof. The platinum wires were laid next to each other such that
the windows are offset (e.g., separated by a diffusion barrier).
The bundle was then placed into a winding machine & silver wire
was wrapped around the platinum electrodes. The silver wire was
then chloridized to produce a silver/silver chloride reference
electrode. The sensor was trimmed to length, and a glucose oxidase
enzyme solution applied to both windows (e.g., enzyme applied to
both sensors). To deactivate the enzyme in one window (e.g., window
904a, FIG. 9B) the window was dipped into dimethylacetamide (DMAC)
and rinsed. After the sensor was dried, a resistance layer was
sprayed onto the sensor and dried.
FIG. 12 shows the results from one experiment, comparing the
signals from the two electrodes of the dual-electrode sensor having
a coiled silver/silver chloride wire reference electrode described
above. The "Plus GOx" electrode included active GOx in its window.
The "No GOx" electrode included DMAC-inactivated GOx in its window.
To test, the sensor was incubated in room temperature phosphate
buffered saline (PBS) for 30 minutes. During this time, the signals
from the two electrodes were substantially equivalent. Then the
sensor was moved to a 40-mg/dl solution of glucose in PBS. This
increase in glucose concentration resulting in an expected rise in
signal from the "Plus GOx" electrode but no significant increase in
signal from the "No GOx" electrode. The sensor was then moved to a
200-mg/dl solution of glucose in PBS. Again, the "Plus GOx"
electrode responded with a characteristic signal increase while no
increase in signal was observed for the "No GOx" electrode. The
sensor was then moved to a 400-mg/dl solution of glucose in PBS.
The "Plus GOx" electrode signal increased to about 5000 counts
while no increase in signal was observed for the "No GOx"
electrode. As a final test, the sensor was moved to a solution of
400 mg/dl glucose plus 0.22 mM acetaminophen (a known interferant)
in PBS. Both electrodes recorded similarly dramatic increases in
signal (raw counts). These data indicate that the "No GOx"
electrode is measuring sensor background (e.g., noise) that is
substantially related to non-glucose factors.
Example 2
Dual-Electrode Sensor with X-Shaped Reference Electrode
This sensor was constructed similarly to the sensor of Example 1,
except that the configuration was similar to the embodiment shown
in FIG. 7J. Two platinum electrode wires were dipped into
non-conductive material and then electroactive windows formed by
removing portions of the nonconductive material. The two wires were
then bundled with an X-shaped silver reference electrode
therebetween. An additional layer of non-conductive material held
the bundle together.
FIG. 13 shows the results from one experiment, comparing the
signals from the two electrodes of a dual-electrode sensor having
an X-shaped reference electrode. The "Plus GOx" electrode has
active GOx in its window. The "No GOx" electrode has
DMAC-inactivated GOx in its window. The sensor was tested as was
described for Experiment 1, above. Signal from the two electrodes
were substantially equivalent until the sensor was transferred to
the 40-mg/dl glucose solution. As this point, the "Plus GOx"
electrode signal increased but the "No GOx" electrode signal did
not. Similar increases were observed in the "Plus GOx" signal when
the sensor was moved consecutively to 200-mg/dl and 400-mg/dl
glucose solution, but still not increase in the "No GOx" signal was
observed. When sensor was moved to a 400-mg/dl glucose solution
containing 0.22 mM acetaminophen, both electrodes recorded a
similar increase in signal (raw counts). These data indicate that
the "No GOx" electrode measures sensor background (e.g., noise)
signal that is substantially related to non-glucose factors.
Example 3
Dual-Electrode Challenge with Hydrogen Peroxide, Glucose and
Acetaminophen
A dual-electrode sensor was assembled similarly to the sensor of
Example 1, with a bundled configuration similar to that shown in
FIG. 7C (two platinum working electrodes and one silver/silver
chloride reference electrode, not twisted). The electroactive
windows were staggered by 0.085 inches, to create a diffusion
barrier.
FIG. 14 shows the experimental results. The Y-axis shows the
glucose signal (volts) and the X-axis shows time. The "Enzyme"
electrode included active GOx. The "No Enzyme" electrode did not
include active GOx. The "Enzyme minus No Enzyme" represents a
simple subtraction of the "Enzyme" minus the "NO Enzyme." The
"Enzyme" electrode measures the glucose-related signal and the
non-glucose-related signal. The "No Enzyme" electrode measures only
the non-glucose-related signal. The "Enzyme minus No Enzyme" graph
illustrates the portion of the "Enzyme" signal related to only the
glucose-related signal.
The sensor was challenged with increasing concentrations of
hydrogen peroxide in PBS. As expected, both the "Enzyme" and "No
Enzyme" electrodes responded substantially the same with increases
in signal corresponding increased in H.sub.2O.sub.2 concentration
(.about.50 .mu.M, 100 .mu.M and 250 .mu.M H.sub.2O.sub.2). When the
"No Enzyme" signal was subtracted from the "Enzyme" signal, the
graph indicated that the signal was not related to glucose
concentration.
The sensor was challenged with increasing concentrations of glucose
(.about.20 mg/dl, 200 mg/dl, 400 mg/dl) in PBS. As glucose
concentration increased, the "Enzyme" electrode registered a
corresponding increase in signal. In contrast, the "No Enzyme"
electrode did not record an increase in signal. Subtracting the "No
Enzyme" signal from the "Enzyme" signal shows a step-wise increase
in signal related to only glucose concentration.
The sensor was challenged with the addition of acetaminophen
(.about.0.22 mM) to the highest glucose concentration.
Acetaminophen is known to be an interferent (e.g., produces
non-constant noise) of the sensors built as described above, e.g.,
due to a lack of acetaminophen-blocking membrane and/or mechanism
formed thereon or provided therewith. Both the "Enzyme" and "No
Enzyme" electrodes showed a substantial increase in signal. The
"Enzyme minus No Enzyme" graph substantially shows the portion of
the signal that was related to glucose concentration.
From these data, it is believed that a dual-electrode system can be
used to determine the analyte-only portion of the signal.
Example 4
IV Dual-Electrode Sensor in Dogs
An intravascular dual-electrode sensor was built substantially as
described in co-pending U.S. Patent application Ser. Nos.
11/543,396, 11/543,490, and 11/543,404 [Pub. Nos. 2008-0119703 A1,
2008-0119704 A1, 2008-0119706 A1], entitled "Analyte sensor" and
filed Oct. 4, 2006. Namely, the sensor was built by providing two
platinum wires (e.g., dual working electrodes) and vapor-depositing
the platinum wires with Parylene to form an insulating coating. A
portion of the insulation on each wire was removed to expose the
electroactive surfaces (e.g., 904a and 904b). The wires were
bundled such that the windows were offset to provide a diffusion
barrier, as described herein, cut to the desired length, to form an
"assembly." A silver/silver chloride reference electrode was
disposed remotely from the working electrodes (e.g., coiled inside
the sensor's fluid connector).
An electrode domain was formed over the electroactive surface areas
of the working electrodes by dip coating the assembly in an
electrode solution (comprising BAYHYDROL.RTM. 123 with PVP and
added EDC)) and drying.
An enzyme domain was formed over the electrode domain by
subsequently dip coating the assembly in an enzyme domain solution
(BAYHYDROL 140AQ mixed with glucose oxidase and glutaraldehyde) and
drying. This dip coating process was repeated once more to form an
enzyme domain having two layers and subsequently drying. Next an
enzyme solution containing active GOx was applied to one window;
and an enzyme solution without enzyme (e.g., No GOx) was applied to
the other window.
A resistance domain was formed over the enzyme domain by
subsequently spray coating the assembly with a resistance domain
solution (Chronothane H and Chronothane 1020) and drying.
After the sensor was constructed, it was placed in a protective
sheath and then threaded through and attached to a fluid coupler,
as described in co-pending U.S. patent application Ser. Nos.
11/543,396, 11/543,490, and 11/543,404 [Pub. Nos. 2008-0119703 A1,
2008-0119704 A1, 2008-0119706 A1], entitled "Analyte sensor" and
filed Oct. 4, 2006. Prior to use, the sensors were sterilized using
electron beam radiation.
The forelimb of an anesthetized dog (2 years old, .about.40 pounds)
was cut down to the femoral artery and vein. An arterio-venous
shunt was placed from the femoral artery to the femoral vein using
14 gauge catheters and 1/8-inch IV tubing. A pressurized arterial
fluid line was connected to the sensor systems at all times. The
test sensor system included a 20 gauge.times.1.25-inch catheter and
took measurements every 30 seconds. The catheter was aseptically
inserted into the shunt, followed by insertion of the sensor into
the catheter. As controls, the dog's glucose was checked with an
SMBG, as well as removing blood samples and measuring the glucose
concentration with a Hemocue.
FIG. 15 shows the experimental results. Glucose test data (counts)
is shown on the left-hand Y-axis, glucose concentration for the
controls (SMBG and Hemocue) are shown on the right-hand y-axis and
time is shown on the X-axis. Each time interval on the X-axis
represents 29-minutes (e.g., 12:11 to 12:40 equals 29 minutes). An
acetaminophen challenge is shown as a vertical line on the
graph.
The term "Plus GOx" refers to the signal from the electrode coated
with active GOx., which represents signal due to both the glucose
concentration and non-glucose-related electroactive compounds as
described elsewhere herein (e.g., glucose signal and background
signal, which includes both constant and non-constant noise). "No
GOx" is signal from the electrode lacking GOx, which represents
non-glucose related signal (e.g., background signal, which includes
both constant and non-constant noise). The "Glucose Only" signal
(e.g., related only to glucose concentration) is determined during
data analysis (e.g., by sensor electronics). In this experiment,
the "Glucose Only" signal was determined by a subtraction of the
"No GOx" signal from the "Plus GOx" signal.
During the experiment, the "No GOx" signal (thin line)
substantially paralleled the "Plus GOx" signal (medium line). The
"Glucose Only" signal substantially paralleled the control tests
(SMBG/Hemocue).
Acetaminophen is known to be an interferent (e.g., produces
non-constant noise) of the sensors built as described above, e.g.,
due to a lack of acetaminophen-blocking membrane and/or mechanism
formed thereon or provided therewith. The SMBG or Hemocue devices
utilized in this experiment, however, do include mechanisms that
substantially block acetaminophen from the signal (see FIG. 15).
When the dog was challenged with acetaminophen, the signals from
both working electrodes ("Plus GOx" and "No GOx") increased in a
substantially similar manner. When the "Glucose Only" signal was
determined, it substantially paralleled the signals of the control
devices and was of a substantially similar magnitude.
From these experimental results, the inventors believe that an
indwelling, dual-electrode glucose sensor system (as described
herein) in contact with the circulatory system can provide
substantially continuous glucose data that can be used to calculate
a glucose concentration that is free from background components
(e.g., constant and non-constant noise), in a clinical setting.
Methods and devices that are suitable for use in conjunction with
aspects of the preferred embodiments are disclosed in U.S. Pat. No.
4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No. 6,001,067; U.S.
Pat. No. 6,741,877; U.S. Pat. No. 6,702,857; U.S. Pat. No.
6,558,321; U.S. Pat. No. 6,931,327; U.S. Pat. No. 6,862,465; U.S.
Pat. No. 7,074,307; U.S. Pat. No. 7,081,195; U.S. Pat. No.
7,108,778; and U.S. Pat. No. 7,110,803.
Methods and devices that are suitable for use in conjunction with
aspects of the preferred embodiments are disclosed in U.S.
Publication No. US-2005-0176136-A1; U.S. Publication No.
US-2005-0251083-A1; U.S. Publication No. US-2005-0143635-A1; U.S.
Publication No. US-2005-0181012-A1; U.S. Publication No.
US-2005-0177036-A1; U.S. Publication No. US-2005-0124873-A1; U.S.
Publication No. US-2005-0115832-A1; U.S. Publication No.
US-2005-0245799-A1; U.S. Publication No. US-2005-0245795-A1; U.S.
Publication No. US-2005-0242479-A1; U.S. Publication No.
US-2005-0182451-A1; U.S. Publication No. US-2005-0056552-A1; U.S.
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US-2006-0020188-A1; U.S. Publication No. US-2006-0036141-A1; U.S.
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US-2006-0142651-A1; U.S. Publication No. US-2006-0086624-A1; U.S.
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US-2006-0040402-A1; U.S. Publication No. US-2006-0036142-A1; U.S.
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US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-A1; U.S.
Publication No. US-2006-0036139-A1; U.S. Publication No.
US-2006-0142651-A1; U.S. Publication No. US-2006-0036145-A1; U.S.
Publication No. US-2006-0036144-A1; U.S. Publication No.
US-2006-0200022-A1; U.S. Publication No. US-2006-0198864-A1; U.S.
Publication No. US-2006-0200019-A1; U.S. Publication No.
US-2006-0189856-A1; U.S. Publication No. US-2006-0200020-A1; U.S.
Publication No. US-2006-0200970-A1; U.S. Publication No.
US-2006-0183984-A1; U.S. Publication No. US-2006-0183985-A1; and
U.S. Publication No. US-2006-0195029-A1.
Methods and devices that are suitable for use in conjunction with
aspects of the preferred embodiments are disclosed in U.S.
application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled
"DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S.
application Ser. No. 11/335,879 filed Jan. 18, 2006 and entitled
"CELLULOSIC-BASED INTERFERENCE DOMAIN FOR AN ANALYTE SENSOR"; U.S.
application Ser. No. 11/334,876 filed Jan. 18, 2006 and entitled
"TRANSCUTANEOUS ANALYTE SENSOR"; U.S. application Ser. No.
11/498,410 filed Aug. 2, 2006 and entitled "SYSTEMS AND METHODS FOR
REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM"; U.S.
application Ser. No. 11/515,443 filed Sep. 1, 2006 and entitled
"SYSTEMS AND METHODS FOR PROCESSING ANALYTE SENSOR DATA"; U.S.
application Ser. No. 11/503,367 filed Aug. 10, 2006 and entitled
"ANALYTE SENSOR"; and U.S. application Ser. No. 11/515,342 filed
Sep. 1, 2006 and entitled "SYSTEMS AND METHODS FOR PROCESSING
ANALYTE SENSOR DATA".
All references cited herein are incorporated herein by reference in
their entireties. To the extent publications and patents or patent
applications incorporated by reference contradict the disclosure
contained in the specification, the specification is intended to
supersede and/or take precedence over any such contradictory
material.
The above description discloses several methods and materials of
the present invention. This invention is susceptible to
modifications in the methods and materials, as well as alterations
in the fabrication methods and equipment. Such modifications will
become apparent to those skilled in the art from a consideration of
this disclosure or practice of the invention disclosed herein.
Consequently, it is not intended that this invention be limited to
the specific embodiments disclosed herein, but that it cover all
modifications and alternatives coming within the true scope and
spirit of the invention as embodied in the attached claims.
* * * * *