Note: Descriptions are shown in the official language in which they were submitted.
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DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR
RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. Application No.
11/004,561 filed December 3, 2004, which claims the benefit of U.S.
Provisional Application
No. 60/527,323 filed December 5, 2003, U.S. Provisional Application No.
60/587,787, filed
July 13, 2004, and U.S. Provisional Application No. 60/614,683, filed
September 30, 2004,
the disclosures of which are hereby expressly incorporated by reference in
their entirety and
are hereby expressly made a portion of this application.
FIELD OF THE INVENTION
[0002] The present invention relates generally to systems and methods for
measuring an analyte concentration in a host.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus is a disorder in which the pancreas cannot create
sufficient insulin (Type I 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 tlie 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.
[0004] 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.
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SUMMARY OF THE INVENTION
[0005] 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.
[0006] 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
exainple, by
increasing accuracy of the device).
[0007] 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
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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.
[00081 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
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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.
[0009] 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
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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
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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.
[0010] 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 detennined. 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
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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
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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.
[0011] 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 beneatli 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.
[0012] In an embodiment of the first aspect, the first working electrode and
the
second working electrode are coaxial.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] 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.
[0017] In an embodiment of the first aspect, the second ends are coaxial.
[0018] In an embodiment of the first aspect, the second ends are stepped.
[0019] 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.
[0020] 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.
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[0021] In an embodiment of the first aspect, the additional electrode is
located at a
position remote from the first and second working electrodes.
[0022] 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.
[0023] In an embodiment of the first aspect, the sensor is configured for
implantation into the host.
[0024] In an embodiment of the first aspect, the sensor is configured for
subcutaneous implantation in a tissue of a host.
[0025] In an embodiment of the first aspect, the sensor is configured for
indwelling in a blood stream of a host.
[0026] In an embodiment of the first aspect, the sensor substantially
continuously
measures an analyte concentration in a host.
[0027] 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.
[0028] 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.
[0029] 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.
[0030] 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.
[0031] 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.
[0032] 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
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least two functions selected from the group consisting of electrical
conductance, insulative
property, structural support, and diffusion barrier.
[0033] 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.
[0034] 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.
[0035] 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.
[0036] 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.
[0037] 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.
[0038] 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
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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.
[0039] In an embodiment of the third aspect, the first working electrode and
the
second working electrode are coaxial.
[0040] 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.
[0041] 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.
[0042] 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.
[0043] 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.
[0044] In an embodiment of the third aspect, the second ends are coaxial.
[0045] In an embodiment of the third aspect, the second ends are stepped.
[0046] 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.
[0047] 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.
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[00481 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.
[0049] 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.
[0050] In an embodiment of the fourth aspect, the non-conductive material is
configured to provide an insulative property and structural support.
[0051] In an embodiment of the fourth aspect, the non-conductive material is
configured to provide an insulative property and a diffusion barrier.
[0052] In an embodiment of the fourth aspect, the sensor fiu-ther comprises a
reference electrode, wherein the reference electrode is configured to provide
a diffusion
barrier and structural support
[0053] In an embodiment of the fourth aspect, the non-conductive material is
configured to provide a diffusion barrier and structural support.
[0054] In an embodiment of the fourth aspect, the sensor further comprises at
least
one of a reference electrode and a counter electrode.
[0055] 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.
[0056] 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.
[0057] 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.
[0058] In an embodiment of the fourth aspect, the sensor is configured for
implantation into the host.
[0059] In an embodiment of the fourth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
[0060] In an embodiment of the fourth aspect, the sensor is configured for
indwelling in a blood stream of the host.
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[0061] In an embodiment of the fourth aspect, the sensor substantially
continuously measures an analyte concentration in the host.
[0062] 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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.
[0068] 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.
[0069] 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.
[0070] 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.
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[0071] 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.
[0072] 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.
[0073] 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.
[0074] 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.
[0075] 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.
[0076] 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.
[0077] In an embodiment of the fifth aspect, the non-conductive material is
configured to provide an insulative property and structural support.
[0078] In an embodiment of the fifth aspect, the non-conductive material is
configured to provide an insulative property and a diffusion barrier.
[0079] In an embodiment of the fifth aspect, the non-conductive material is
configured to provide a diffusion barrier and structural support.
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[0080] 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.
[0081] 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.
[0082] In an embodiment of the sixth aspect, the physical diffusion barrier
comprises the insulator.
[0083] In an embodiment of the sixth aspect, the physical diffusion barrier
comprises the reference electrode.
[0084] 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.
[0085] In an embodiment of the sixth aspect, the physical diffusion barrier
comprises a membrane.
[0086] 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.
[0087] 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.
[0088] 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
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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.
[0089] 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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] 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.
[0094] 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.
[0095] 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.
[0096] In an embodiment of the sixth aspect, the sensor fiuther comprises at
least
one of a reference electrode and a counter electrode.
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[0097] 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.
[0098] 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.
[0099] 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 worlcing electrode.
[0100] In an embodiment of the sixth aspect, the sensor is configured for
implantation into the host.
[0101] In an embodiment of the sixth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
[0102] In an embodiment of the sixth aspect, the sensor is configured for
indwelling in a blood stream of the host.
[0103] In an embodiment of the sixth aspect, sensor substantially continuously
measures an analyte concentration in the host.
[0104] 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.
[0105] 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.
[0106] 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.
[0107] 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.
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[0108) 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.
[0109] 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.
[0110] 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.
[0111] 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.
[0112] 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.
1
[0113] 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.
[0114] In an embodiment of the seventh aspect, the analyte sensor is
configured to
indwell in a blood stream of the host, and wherein the diffiision barrier
comprises a
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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.
[0115] In an embodiment of the seventh aspect, the sensor further comprises at
least one of a reference electrode and a counter electrode.
[0116] In an embodiment of the seventh aspect, the sensor is configured for
implantation into the host.
[0117] In an embodiment of the seventh aspect, the sensor substantially
continuously measures an analyte concentration in the host.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
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[0122] In an embodiment of the eighth aspect, the non-glucose related noise is
substantially non-constant.
[0123] In an embodiment of the eighth aspect, the electronics are configured
to
substantially remove noise caused by mechanical factors.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[01291 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.
[0130] In an embodiment of the eighth aspect, the electronics comprise a
differential amplifier configured to electronically subtract the second signal
from the first
signal.
[0131] 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.
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[0132] 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.
[0133] 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. 1
[0134] 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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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.
[0139] 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 .
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[0140] In an embodiment of the ninth aspect, the non-glucose related noise is
substantially non-constant.
[0141] 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.
[0142] In an embodiment of the ninth aspect, the electronics are configured to
substantially remove noise caused by mechanical factors.
[0143] 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.
[0144] 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.
[0145] 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.
[0146] 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.
[0147] 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.
[0148] In an embodiment of the ninth aspect, the sensor further comprises at
least
one of a reference electrode and a counter electrode.
[0149] 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.
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[0150] 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.
[0151] 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.
[0152] In an embodiment of the ninth aspect, the sensor is configured for
implantation into the host.
[0153] In an embodiment of the ninth aspect, the sensor is configured for
subcutaneous implantation in a tissue of the host.
[0154] In an embodiment of the ninth aspect, the sensor is configured for
indwelling in a blood stream of the host.
[0155] In an embodiment of the ninth aspect, the sensor substantially
continuously
measures an analyte concentration of the host.
[0156] 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.
[0157] 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.
[0158] 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.
[0159] 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.
[0160] 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.
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[0161] 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.
[0162] 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.
[0163] 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.
[0164] 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.
[0165] 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
[0166] Fig. 1A is a perspective view of a continuous analyte sensor, including
an
implantable body with a membrane system disposed thereon
[0167] Fig. 1B is an expanded view of an alternative embodiment of a
continuous
analyte sensor, illustrating the in vivo portion of the sensor.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] 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.
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[0172] Fig. 4 is a block diagram that illustrates continuous glucose sensor
electronics in one embodiment.
[0173] Fig. 5 is a drawing of a receiver for the continuous glucose sensor in
one
embodiment.
[0174] Fig. 6 is a block diagram of the receiver electronics in one
embodiment.
[0175] Fig. 7A 1 is a schematic of one embodiment of a coaxial sensor having
axis
A-A.
[0176] Fig. 7A2 is a cross-section of the sensor shown in Fig. 7A1.
[0177] Fig. 7B is a schematic of another embodiment of a coaxial sensor.
[0178] Fig. 7C is a schematic of one embodiment of a sensor having three
electrodes.
[0179] Fig. 7D is a schematic of one embodiment of a sensor having seven
electrodes.
[0180] Fig. 7E is a schematic of one embodiment of a sensor having two pairs
of
electrodes and insulating material.
[0181] Fig. 7F is a schematic of one embodiment of a sensor having two
electrodes separated by a reference electrode or insulating material.
[0182] Fig. 7G is a schematic of another embodiment of a sensor having two
electrodes separated by a reference electrode or insulating material.
[0183] Fig. 7H is a schematic of another embodiment of a sensor having two
electrodes separated by a reference electrode or insulating material.
[0184] Fig. 71 is a schematic of another embodiment of a sensor having two
electrodes separated by reference electrodes or insulating material.
[0185] 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.
[0186] 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.
[0187] Fig. 7L is a schematic of one embodiment of a sensor having two
electrodes embedded in an insulating material.
[0188] Fig. 7M is a schematic of one embodiment of a sensor having multiple
working electrodes and multiple reference electrodes.
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[0189] 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.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] 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 H202 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).
- - - [0195] Fig. 11 is a schematic illustrating one embodiment of a triple
helical
coaxial sensor having a stepped second terminus for engaging the sensor
electronics.
[0196] 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.
[0197] 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.
[0198] 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).
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[0199] 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
[0200] 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
[0201] In order to facilitate an understanding of the disclosed invention, a
number
of terms are defined below.
[0202] 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-
13 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,
DuchenneBecker
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-
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deoxycortisol); desbutylhalofantrine; dihydropteridine reductase;
diptheria/tetanus antitoxin;
erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty
acids/acylglycines; free !3-
human chorionic gonadotropin; free erythrocyte porphyrin; free thyroxine
(FT4); free tri-
iodothyronine (FT3); fumarylacetoacetase; galactose/gal-l-phosphate; galactose-
l-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 phosplioribosyl transferase; immunoreactive trypsin; lactate;
lead; lipoproteins
((a), B/A-1, B); 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 duodenalisa,
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),
cruzi/rangeli,
Schistosoma mansoni, Toxoplasma gondii, Trepenoma pallidium, Trypanosoma
vesicular stomatis 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
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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).
[0203] 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. Patent 6,001,067, for example.
[0204] 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.
[0205] 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.
[0206] 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.
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[0207] 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.
[0208] 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.
[0209] 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.
[0210] 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.
[0211] 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
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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
electrocheinically reactive surfaces of the working and optionally reference
electrodes.
[0212] 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.
[0213] 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.
[0214] 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
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that electrically connect the electrochemically reactive surface to connectors
(for connecting
the sensor to electronics) or to the electronics.
[0215] 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.
[0216] 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.
[0217] 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.
[0218] 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
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membrane system that covers an electrochemically reactive surface, the
electrolyte domain is
located more proximal to the electrochemically reactive surface than the
resistance domain.
[0219] 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.
[0220] 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.
[0221] 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.
[0222] 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.
[0223] 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.
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[0224] 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).
[0225] The term "RAM" as used herein is a broad term, and is to be given its
ordinary and customaiy 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.
[0226] 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.
[0227] 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.
[0228] 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.
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[0229] 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 streain 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.
[0230] 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. Patent
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.
[0231] 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.
[0232] 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.
[0233] 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
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(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.
[0234] 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.
[0235] 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.
[02361 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).
[0237) 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.
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[0238] 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.
[0239] The term "reference analyte values" and "reference data" as used herein
are
broad tenns, 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.
[0240] 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).
[0241] 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
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produced during cell metabolism and/or wound healing, electroactive species
that arise during
body pH changes and the like.
[0242] 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.
[0243] 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.
[0244] 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.
[0245] 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).
[0246] 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.
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[0247] 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.
[0248] 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.
[0249] 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). ~
[0250) 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
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limited to a special or customized meaning), and refers without limitation to
having a
common axis, having coincident axes or mounted on concentric shafts.
[0251] 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.
[0252] 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.
[0253] 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.
[0254] 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.
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[0255] 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.
[0256] 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-coristarit) "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).
[0257] 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.
[0258] 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
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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.
[0259] 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).
[0260] 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.
[0261] 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
[0262] 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.
[0263] 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
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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.
[0264] 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
H202 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 (xl, yl; X2, Y2) 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-Al.
[0265] 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
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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.
[0266] 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 exainple, 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.
[0267] 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
[0268] 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
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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.
[0269] Preferably, each exemplary sensor design (e.g., Figs. lA, 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.
[0270] 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 (H202) reacts with the surface of
the working
electrode producing two protons (2H+), two electrons (2e ) and one molecule of
oxygen (02),
which produces the electronic current being detected.
[0271] 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
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(additional) working electrode is configured to measure a background signal,
including
constant and non-constant analyte signal components.
[0272] Preferably, each exemplary sensor design (e.g., Figs. lA, 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.
[0273] Preferably, each exemplary sensor design (e.g., Figs. lA, 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 Bellafonte, PA.
[0274] 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,
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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.
[0275] 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 protectiori 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-Al.
[0276] 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-Al, 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
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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.
[0277] 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-
Al describes biointerface and membrane system configurations and materials
that may be
applied to the preferred embodiments.
Electrode Domain
[0278] 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
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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.
[0279] 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.
[0280] 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 C.
[0281] 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.
[0282] 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 C to about 55 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 fiinctional
coating. However, values outside of those set forth above can be acceptable or
even desirable
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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 C under
vacuum for 20 minutes.
[0283) 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
[0284] 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.
[0285] 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.
[0286] 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
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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.
[0287] 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.
[0288] 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.
[0289] In some alternative embodiments, additional polymers, such as Nafion ,
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 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
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coating at least one layer Nafion 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.
[0290) 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.
[0291] 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-Al, U.S. Publication No. US-2005-0161346-Al, and U.S. Publication No.
US-
2005-0143635-Al. In some alternative embodiments, a distinct interference
domain is not
included. '
[0292) 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,
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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.
[0293] 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.
[0294] 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
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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.
[0295] 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
[0296] 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.
[0297] 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-Al.
[0298] 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,
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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 enzyine 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 C to about 55 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 f-unctional 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 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
[0299] 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.
[0300] 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
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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.
[0301] 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)).
[0302] 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.
[0303] 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
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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.
[0304] 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.
[0305] In some embodiments, the resistance domain is formed from a silicone
polymer modified to allow analyte (e.g., glucose) transport.
[0306] 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. Patent 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
PLURONICO
brand of polymers available from BASFO. In one embodiment, PLURONICO F-127 is
used.
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Other PLURONIC polymers include PPO-PEO-PPO triblock copolymers (e.g.,
PLURONIC R products). Other suitable commercial polymers include, but are not
limited
to, SYNPERONICS products available from UNIQEMA .
[0307] 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.
[0308] 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 uriderlying enzyme of the enzyme domain. Tetrahydrofiiran (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.
[0309] Preferably, each exemplary sensor design (e.g., Figs. lA, 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,
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non-coaxial sensors can be implemented with the sensor system of the preferred
embodiments.
[0310] 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-Al and
U.S.
Application No. 11/360,250 filed February 22, 2006 and entitled "ANALYTE
SENSOR,"
which are incorporated in their entirety herein by reference.
Exemplary Continuous Sensor Configurations
[0311] 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 (H202) as a by product, H202 reacts with
the surface of
the working electrode producing two protons (2H), two electrons (2e") and one
molecule of
oxygen (02) 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 H202 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.
[0312] Some alternative analyte sensors that can benefit from the systems and
methods of the preferred embodiments include U.S. Patent No. 5,711,861 to Ward
et al., U.S.
Patent No. 6,642,015 to Vachon et al., U.S. Patent No. 6,654,625 to Say et
al., U.S. Patent
6,565,509 to Say et al. , U.S. Patent No. 6,514,718 to Heller, U.S. Patent No.
6,465,066 to
Essenpreis et al., U.S. Patent No. 6,214,185 to Offenbacher et al., U.S.
Patent No. 5,310,469
to Cunningham et al., and U.S. Patent No. 5,683,562 to Shaffer et al., S.
Patent 6,579,690 to
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Bonnecaze et al., U.S. Patent 6,484,046 to Say et al. , U.S. Patent 6,512,939
to Colvin et al.,
U.S. Patent 6,424,847 to Mastrototaro et al., U.S. Patent 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.
[0313] 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.
[0314] Fig. lA 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 l0a includes a body 12 and a
sensing region 14
including membrane and electrode systems configured to measure the analyte. In
this
embodiment, the sensor l0a 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-Al; 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. Patent
Number
6,001,067 issued December 14, 1999 and entitled."DEVICE AND METHOD FOR
DETERMINING ANALYTE LEVELS," each of which are incorporated herein by
reference
in their entirety.
[0315] The body 12 of the sensor l0a 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-Al discloses suitable configurations for the body, and is incorporated
by reference
in its entirety.
[0316] 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
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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.
[0317] Preferably, a membrane system (see Fig. 2A) is deposited over the
electroactive surfaces of the sensor l0a 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.
[0318] 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 H202. Glucose oxidase catalyzes the
conversion
of oxygen and glucose to hydrogen peroxide and gluconate according to the
following
reaction:
Glucose + Oa --> Gluconate + H202
[0319] The change in H20Z can be monitored to determine glucose concentration
because for each glucose molecule metabolized, there is a proportional change
in the product
H202 (see Fig. 10). Oxidation of H202 by the working electrode is balanced by
reduction of
ambient oxygen, enzyme generated H202, or other reducible species at the
counter electrode.
The H202 produced from the glucose oxidase reaction further reacts at the
surface of the
working electrode and produces two protons (2H+), two electrons (2e'), and one
oxygen
molecule (Oa). 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
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produced at the working electrode (and flows through the circuitry to the
counter electrode) is
substantially proportional to the amount of H202 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.
[0320] Fig. 1B is a schematic view of an alternative exemplary embodiment of a
continuous analyte sensor lOb, 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 enlbodiment, the in vivo portion of the sensor lOb 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 lOb. 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 lOb 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 systeni, 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.
[0321] 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)
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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).
[0322] 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.
[0323] 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.
[0324] 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.
[0325] 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
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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.
[03261 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
Fig. 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.
[0327] 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
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No. US-2005-0245799-Al. 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.
[0328] 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.
[0329] 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.
ExemplarX Sensor Configurations
[0330] 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.
[0331] 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
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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.
[0332] 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.
[0333] 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 El, 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 El can be dipped into a solution of
insulating polymer
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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 Efa) 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 El 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 El mates (e.g., slides
into) with the first
electrode El, 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 El is a reference or auxiliary electrode, and
the second
electrode E2 is a working electrode. However, the first electrode El 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
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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).
[0334] 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 (El, 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 (El, 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 or other angle)
to expose the
electrode tips to varying extents, as described herein.
[0335] Fig. 7C is a schematic of an exemplary embodiment of a sensor having
three bundled electrodes El, 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.
[0336] 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
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electrodes of a first type (e.g., 3 x El) and three electrodes of a second
type (e.g., 3 x 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 El 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 El, E2, and E3 electrodes
can be used
(e.g., two El 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).
[0337] 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 x El
and 2 x 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 El electrodes can be
working electrodes
and the pair of E2 electrodes can be reference and/or auxiliary electrodes. In
one exemplary
embodiment, the El 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 El electrode includes active GOx and measures a glucose-
related signal;
the other El electrode lacks active GOx and measures a non-glucose-related
signal, and the
E2 electrodes are reference electrodes. In yet another exemplary embodiment,
one El
electrode detects glucose and the other El electrode detects urea, and both E2
electrodes are
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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.
[0338] 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
El, 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 El, 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 El, 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 El, 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 El, 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.
[0339] 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 El, 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
fornied 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,
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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 El 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 El
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.
[0340] 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 El, 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 El, 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 RII 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 El, 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.
[0341] 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 El to the second working electrode E2, around a portion of
the
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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 El, 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., El, 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 El 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., El) 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.
[0342] 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.
71. 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
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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 elec,trode 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).
[0343] 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 El, 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 th-e art appreciates a variety of alternative conf gurations. 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
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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 El, 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 H202
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.
[0344] 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 El, 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 El, 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.
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[0345] 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., El, E2, E3) that are layered with a plurality of
reference electrodes
(e.g., Rl, 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 ureate), 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 Ri
is active only when the first working electrode El 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.
[0346] 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 (El, E2) and optionally a reference electrode R are
embedded in a
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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 configuratiori and operating
requirements (e.g.,
voltage and/or current requirements).
[0347] 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 El, 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
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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).
[0348] 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., (El + E2) x 1 = R or (El + E2) x 2= R,
etc.).
[0349] 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 El 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
El, within electrical connector 804c.
[0350] 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
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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.
[0351] 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 El
may be either
the longest electrode (e.g., connect to electrical contact 804c) or the
shortest electrode (e.g.,
connect to electrical contact 804a).
[0352] Fig. 9A is a schematic view that illustrates yet another exemplary
embodiment of an integrally formed analyte sensor. Namely, two working
electrodes El, 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 El, E2 within the
reference
electrode R cylinder. In alternative embodiments, a reference electrode can be
rolled or
coiled around the working electrodes El, 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.
[0353] Fig. 9B illustrates another embodiment of an integrally formed analyte
sensor. Namely, two working electrodes El, 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 El, E2
within the
reference electrode R coil.
[0354] 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 El, E2.
Portions of
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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).
[0355] 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., H202) 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 H202 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 H202 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.
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[0356] 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.
[0357] 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.
[0358] 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).
[0359] 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 El
(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 El (e.g., in window 904a) is inactive,
electroactive species
(e.g., H202) will not be substantially generated at window 904a (e.g., the
first electrode El
generates substantially no H202 to effect the second electrode E2). In
contrast, the active
enzyme on the second electrode E2 (in window 904b) generates H202 which at
least partially
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diffuses down streanl (away from the windows) and thus has no effect on the
first electrode
El, other features and advantages of spatial diffusion barriers are described
in more detail
elsewhere herein.
[0360] 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
El (window 904a) is active and the enzyine coating on electrode E2 (in window
904b) is
inactive. Because window 904a is located farther downstream than window 904b,
the H202
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, H202
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 H202 produced on electrode El.
[0361] 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 El 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 El 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 El 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.
[0362] 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 El, E2 and E3 are twisted to form a
helix, such as a
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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 El
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 exainple, one of
the electrodes El,
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.
[0363] 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 Figures 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.
[0364] Fig. 7L illustrates an embodiment in which the reference and/or counter
electrode is located remotely from the first and second working electrodes El
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 El, 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.
[0365] 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
entitled
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"ANALYTE SENSOR" and filed on even date herewith, 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.
[0366] 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.
[0367] 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.
[0368) 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
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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 _/ ,_
filed on
even date herewith and entitled "ANALYTE SENSOR." 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.
[0369] 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.
[0370] 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 H2O2, 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 HZO2 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
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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
11/503,367
filed August 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.
[0371] 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 H202, 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 H202 includes H202 from sources
other than the
glucose-GOx reaction; such as but not limited to H202 released by nearby cells
during the
course of the cells' metabolism, H202 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 H2O2.
[0372] 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-
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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
worlcing electrodes.
The electronics are configured to provide the first and second signals that
are used to generate
glucose concentration data substantially witliout 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-Al, US-2005-0203360-Al and US-2006-0036142-A1
describe systems and methods -for processing sensor analyte data and" are
incorporated herein
by reference in their entirety.
[0373] 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.,
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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.
Bifunctionalitv
[0374] 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.
[0375] 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.
[0376] 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).
[0377] 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 tothe
configuration of the
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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.
[0378] 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 [describe its
bifunctionality without
unnecessary characterizations (e.g., not "pancake-shaped"). Fig. 7N through
Fig. 9 illustrate
additional sensor embodiments, wherein the electrodes provide electrical
conductance and
support the sensor's needle-like shape.
[0379] 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.
[0380] 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., 1) acts as an
insulator, to prevent
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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.
[0381] 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., H202)
between the first and
second working electrodes. For example, a sheet of a polymer through which
H202 cannot
diffuse can be interposed between the two working electrodes. Diffusion
barriers are
discussed in greater detail elsewhere herein.
[0382] 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., H202) 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 H202 produced at the first working
electrode cannot
diffuse to the second working electrode, and thereby significantly affect the
second working
electrode's function.
[0383] 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
H202 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).
[0384] 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
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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).
[0385] 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.
[0386] 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., H202) 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., H202) 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 H202
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.
[0387] 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
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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). '
[0388] 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 El, 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 El and
E2 from making direct contact with each other as well as giving the needle-
like sensor its
overall dimensions and shape.
[0389] Fig. 7N illustrates one method of configuring a sensor having a non-
conductive material I that both provides electrical insulation between the
electrodes El, 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).
[0390] 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., H202)
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 El, E2 are placed
in the groves
carved into a cylinder of non-conductive material I. The distance D from El to
E2 (e.g.,
around I) is sufficiently great that H202 produced at El cannot diffuse to E2
and thereby
cause an aberrant signal at E2.
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[0391] 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.
[0392] In preferred embodiments, the sensor is configured for implantation
into
the host. The sensor cain 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).
[0393] 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
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embodiments, the non-glucose related electroactive species include an
interfering species,
non-reaction-related hydrogen peroxide, and/or other electroactive species.
[0394] 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.
[0395] 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 exainple, 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.
[0396] 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).
[0397] 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., H202) 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 H202) from the
first working
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electrode El 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 HZ02 from diffusing from the first working electrode El 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 H202 from
diffusing from the first working electrode El 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
H202 diffuses from
the first working electrode El to the second working electrode E2, the second
working
electrode E2 will not substantially be influenced by the HzOa from the first
working electrode
El..
[0398] 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 El 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, H202 cannot substantially pass
through a
silver/silver chloride reference electrode. In another example, a parylene
insulator can
prevent H202 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 El can be activated for a period of
one second,
followed by activating the second electrode E2 three seconds later (e.g.,
after El has been
inactivated) for a period of one second.
[0399] 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).
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[0400] 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 H202).
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.
[0401] 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 H202 cannot
substantially diffuse
around the reference electrode. Accordingly, H202 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
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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
[0402] 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
otlier
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.
[0403] 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.
[0404] 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).
[0405] 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
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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 in-active 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).
[0406] 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-Al and co-pending
U.S.
Application No. 11/503,367 filed August 10, 2006 and entitled "ANALYTE
SENSOR,"
herein incorporated by reference in its entirety.
[0407] 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.
[0408] 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.
[0409] Referring now to Fig. 9B, in another embodiment, the sensor has a first
working electrode El 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
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second electrode is non-enzymatic or contains inactivated enzyme, which is
depicted
schematically as ova1904b (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., El, E2,
etc.) is connected to sensor electronics (not shown) by a connector 804. Since
the first
electrode El 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).
[0410] 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
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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.
[0411] 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.
[0412] 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 H202, which is produced according to the reaction of glucose with
GOx and
subsequently transfers electrons to the first working electrode (e.g., El;
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 H2OZ (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).
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Furthermore, the sensor has a diffusion barrier that substantially blocks
diffusion of glucose
or H202 between the first and second working electrodes.
Diffusion Barrier
[0413] Another aspect of the sensor is a diffusion barrier, to prevent an
undesired
species, such as H202 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.
[0414] 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
El is coated with an enzyme layer 1000 comprising active enzyme. For example,
in a
glucose sensor, the first working electrode El is coated with glucose oxidase
enzyme (GOx).
A second working electrode E2 is separated from the first working electrode El
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.
[0415] Glucose and oxygen diffase into the enzyme layer 1000, where they react
with GOx, to produce gluconate and H202. At least a portion of the H202
diffuses to the first
working electrode El, where it is electrochemically oxidized to oxygen and
transfers two
electrons (e.g., 2e ) to the first working electrode El, which results in a
glucose signal that is
recorded by the sensor electronics (not shown). The remaining H202 can diffuse
to other
locations in the enzyme layer or out of the enzyme layer (illustrated by the
wavy arrows).
Without a diffitsion barrier D, a portion of the H202 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).
[0416] Preferred embodiments provide for a substantial diffusion barrier D
between the first and second working electrodes (El, E2) such that the H202
cannot
substantially diffuse from the first working electrode El to the second
working electrode E2.
Accordingly, the possibility of an aberrant signal produced by H202 from the
first working
electrode El (at the second working electrode E2) is reduced or avoided.
[0417] In some alternative embodiments, the sensor is provided with a spatial
diffusion barrier between electrodes (e.g., the working electrodes). For
example, a spatial
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diffusion barrier can be created by separating the first and second working
electrodes by a
distance that is too great for the H202 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.
[0418] Figs. 9A and 9B illustrate two exemplary embodiments of sensors with
spatial diffusion barriers. In each embodiment, the sensor has two working
electrodes El 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
enzynze (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 chemioally-
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 w'ide such that H202 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).
[0419] 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.
[0420] 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
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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).
H202 is produced on the working electrode with active GOx. If the H202
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
filed on even date herewith and entitled "ANALYTE SENSOR," herein
incorporated in its entirety by reference.
[0421] 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, H2O2 produced at electroactive surface 904b would
be carrier down
stream (e.g., away from electroactive surface 904a) and thus not affect
electrode El.
[0422] 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 El. The electroactive surface 904b on the
second working
electrode E2 has no active GOx. Accordingly, H202 produced at electroactive
surface 904a is
carried away by the blood flow, and has no substantial effect on the second
working electrode
E2.
[0423] 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 H202
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-
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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.).
[0424] 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 H202 produced at the first working electrode El (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 El (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 H202 produced at one electrode cannot substantially
diffuse to
another electrode. (e.g., from El to either E2 or E3; or from E2 to either El
or E3, etc.).
[0425] 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 -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.
[0426] 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., H202) 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
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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.
[0427] 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.
[0428] 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 el-ectrbde 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.
[0429] 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 H202). 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
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[0430] 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
[0431] 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.
[0432] 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 02 above the counter
electrode (if
applicable) by the oxidation of glucose with glucose oxidase.
[0433] 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
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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.
[0434] 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
[0435] 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.
[0436] 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.
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[0437] 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.
[0438] 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 EEPROIVI 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.
[0439] 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
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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.
[0440] 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
[0441] 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.
[0442] 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."
[0443] 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,
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transmission 52 from the RF transceiver 50 shown in Fig. 4). Once received, a
microprocessor 66 can process the signals, such as described below.
[0444] 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 com 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. - -
[0445] 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.
[0446] 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.
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[0447] 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.
[0448] 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.
[0449] 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
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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
[0450] 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.
[0451] 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 menibrane, such as described in U.S. Publication
No. US-2005-
0 1 12169-A l, 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.
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[0452] 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.
[04531 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.
[0454] 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.
[0455) 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
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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.
[0456] 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 oxygeri=measuririg 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.
[0457] 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.
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[0458] 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.
[0459] 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.
[0460] 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).
[0461] 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.
[0462] 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.
[0463] In some embodiments, the signal from the oxygen measuring electrode
may be digitally low-pass filtered (for example, with a passband of 0-10-$ Hz,
dc-24 hour
cycle lengths) to remove transient fluctuations in oxygen, due to local
ischemia, postural
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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.
[0464] 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-Al, 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.
[0465] 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.
[0466] 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
witli 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
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electrode to obtain the signal contribution due to glucose only according to
the following
equation:
Signal glucose only = Signal glucose-measuring working electrode - Signal
baseline-measuring working electrode
[0467] 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.
[0468] One aspect the preferred embodiments provides for a simplified
calibration
technique, wherein the variability of the baseline has been eliminated
(namely, subtracted).
Nanlely, calibration of the resultant differential signal (Signal glucose
only) can be performed
with a single matched data pair by solving the following equation:
y=mx
[0469] 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.
[04701 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 = nzx + 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
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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.
[0471] 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 na of
the glucose signal. Consequently, a shift in baseline may be indicative of a
change in
sensitivity na. 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.
[0472) It is noted that infrequent new niatching 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).
[04731 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 measux'ed (for example, interfering
species), which
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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. Patent No.
4,776,944, U.S.
Patent No. 5,356,786, U.S. Patent No. 5,593,852, U.S Patent No. 5776324B 1,
and U.S. Patent
No. 6,356,776).
[0474] 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.
[0475] In summary, the system and methods of the preferred embodiments
simplify the coinputation 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).
[0476] 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-
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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
[0477] 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.
[0478] 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 0.22mM 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.
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Example 2: Dual-Electrode Sensor with X-Shaped Reference Electrode
[04791 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.
[0480] 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 GQx" signal when the sensor was timoved 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 backgrourid (e.g., noise) signal that is
substantially related to
non-glucose factors.
Example 3: Dual-Electrode Challenge with Hydrogen Peroxide, Glucose, and
Acetaminophen
[0481] 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.
[0482] 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
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Enzyme" graph illustrates the portion of the "Enzyme" signal related to only
the glucose-
related signal.
[0483] 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
HZO2 concentration
(-50 M, 100 M and 250 M HZOZ). When the "No Enzyme" signal was subtracted
from
the "Enzyme" signal, the graph indicated that the signal was not related to
glucose
concentration.
[0484] The sensor was challenged with increasing concentrations of glucose (-
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.
[0485] The sensor was challenged with the addition of acetaminophen (-.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.
[0486] 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
[0487] An intravascular dual-electrode sensor was built substantially as
described
in co-pending U.S. Patent application / ,_ filed on even date herewith and
entitled
"ANALYTE SENSOR." 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).
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[0488] 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 123 with PVP and added EDC)) and drying.
[0489] 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.
[0490] 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.
[0491] 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 / , filed on even date herewith and entitled "ANALYTE SENSOR."
Prior to use, the sensors were sterilized using electron beam radiation.
[0492] The forelimb of an anesthetized dog (2 years old, -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 x 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.
[0493] 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.
[0494] 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
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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.
[0495] 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).
[0496] 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.
[0497] 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.
[0498] Methods and devices that are suitable for use in conjunction with
aspects
of the preferred embodiments are disclosed in U.S. Patent No. 4,994,167; U.S.
Patent No.
4,757,022; U.S. Patent No. 6,001,067; U.S. Patent No. 6,741,877; U.S. Patent
No. 6,702,857;
U.S. Patent No. 6,558,321; U.S. Patent No. 6,931,327; U.S. Patent No.
6,862,465; U.S. Patent
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.
[0499] 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-
Al;
U.S. Publication No. US-2005-0124873-Al; U.S. Publication No. US-2005-0115832-
A1;
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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. Publication No. US-2005-0192557-
Al;
U.S. Publication No. US-2005-0154271-A1; U.S. Publication No. US-2004-0199059-
A1;
U.S. Publication No. US-2005-0054909-A1; U.S. Publication No. US-2005-0112169-
A1;
U.S. Publication No. US-2005-0051427-A1; U.S. Publication No. US-2003-0032874-
A1;
U.S. Publication No. US-2005-0103625-Al; U.S. Publication No. US-2005-0203360-
A1;
U.S. Publication No. US-2005-0090607-A1; U.S. Publication No. US-2005-0187720-
A1;
U.S. Publication No. US-2005-0161346-A1; U.S. Publication No. US-2006-0015020-
Al;
U.S. Publication No. US-2005-0043598-A1; U.S. Publication No. US-2003-0217966-
A1;
U.S. Publication No. US-2005-0033132-A1; U.S. Publication No. US-2005-0031689-
A1;
U.S. Publication No. US-2004-0186362-A1; U.S. Publication No. US-2005-0027463-
Al;
U.S. Publication No. US-2005-0027181-A1; U.S. Publication No. US-2005-0027180-
A1;
U.S. Publication No. US-2006-0020187-A1; U.S. Publication No. US-2006-0036142-
A1;
U.S. Publication No. US-2006-0020192-Al; U.S. Publication No. US-2006-0036143-
A1;
U.S. Publication No. US-2006-0036140-A1; U.S. Publication No. US-2006-0019327-
Al;
U.S. Publication No. US-2006-0020186-A1; U.S. Publication No. US-2006-0020189-
A1;
U.S. Publication No. US-2006-0036139-A1; U.S. Publication No. US-2006-0020191-
A1;
U.S. Publication No. US-2006-0020188-A1; U S: Publication No. US-2006-0036141-
A1;
U.S. Publication No. US-2006-0020190-A1; U.S. Publication No. US-2006-0036145-
Al;
U.S. Publication No. US-2006-0036144-Al; U.S. Publication No. US-2006-0016700-
A1;
U.S. Publication No. US-2006-0142651-A1; U.S. Publication No. US-2006-0086624-
A1;
U.S. Publication No. US-2006-0068208-Al; U.S. Publication No. US-2006-0040402-
A1;
U.S. Publication No. US-2006-0036142-Al; U.S. Publication No. US-2006-0036141-
Al;
U.S. Publication No. US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-
A1;
U.S. Publication No. US-2006-0036139-Al; U.S. Publication No. US-2006-0142651-
Al;
U.S. Publication No. US-2006-0036145-A1; U.S. Publication No. US-2006-0036144-
A1;
U.S. Publication No. US-2006-0200022-Al; 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-Al; U.S. Publication No. US-2006-0200970-
A1;
U.S. Publication No. US-2006-0183984-A1; U.S. Publication No. US-2006-0183985-
Al; and
U.S. Publication No. US-2006-0195029-A1.
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WO 2008/041984 PCT/US2006/038820
[0500] Methods and devices that are suitable for use in conjunction with
aspects
of the preferred embodiments are disclosed in U.S. Application No. 09/447,227
filed
November 22, 1999 and entitled "DEVICE AND METHOD FOR DETERMINING
ANALYTE LEVELS"; U.S. Application No. 11/335,879 filed January 18, 2006 and
entitled
"CELLULOSIC-BASED INTERFERENCE DOMAIN FOR AN ANALYTE. SENSOR"; U.S.
Application No. 11/334,876 filed January 18, 2006 and entitled "TRANSCUTANEOUS
ANALYTE SENSOR"; U.S. Application No. 11/498,410 filed August 2, 2006 and
entitled
"SYSTEMS AND METHODS FOR REPLACING SIGNAL ARTIFACTS IN A GLUCOSE
SENSOR DATA STREAM"; U.S. Application No. 11/515,443 filed September 1, 2006
and
entitled "SYSTEMS AND METHODS FOR PROCESSING ANALYTE SENSOR DATA";
U.S. Application No. 11/503,367 filed August 10, 2006 and entitled "ANALYTE
SENSOR";
and U.S. Application No. 11/515,342 filed September 1, 2006 and entitled
"SYSTEMS AND
METHODS FOR PROCESSING ANALYTE SENSOR DATA".
[0501] 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.
[0502] The above description discloses several methods and materials of the
present invention. This invention is susceptible to modificati ns 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.
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