U.S. patent application number 17/132664 was filed with the patent office on 2021-06-24 for analyte sensor.
The applicant listed for this patent is DexCom, Inc.. Invention is credited to Apurv Ullas Kamath, Ying Li, Peter C. Simpson, Richard C. Yang.
Application Number | 20210186383 17/132664 |
Document ID | / |
Family ID | 1000005636415 |
Filed Date | 2021-06-24 |
United States Patent
Application |
20210186383 |
Kind Code |
A1 |
Simpson; Peter C. ; et
al. |
June 24, 2021 |
ANALYTE SENSOR
Abstract
Systems and methods of use for continuous analyte measurement of
a host's vascular system are provided. In some embodiments, a
continuous glucose measurement system includes a vascular access
device, a sensor and sensor electronics, the system being
configured for insertion into communication with a host's
circulatory system.
Inventors: |
Simpson; Peter C.; (Cardiff,
CA) ; Li; Ying; (San Diego, CA) ; Kamath;
Apurv Ullas; (San Diego, CA) ; Yang; Richard C.;
(Carlsbad, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DexCom, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
1000005636415 |
Appl. No.: |
17/132664 |
Filed: |
December 23, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16526910 |
Jul 30, 2019 |
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17132664 |
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16036808 |
Jul 16, 2018 |
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16526910 |
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14072659 |
Nov 5, 2013 |
10052055 |
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16036808 |
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12267525 |
Nov 7, 2008 |
8626257 |
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14072659 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 5/1723 20130101;
A61B 5/14546 20130101; A61B 5/6866 20130101; A61B 5/1495
20130101 |
International
Class: |
A61B 5/1495 20060101
A61B005/1495; A61B 5/145 20060101 A61B005/145; A61B 5/00 20060101
A61B005/00; A61M 5/172 20060101 A61M005/172 |
Claims
1-18. (canceled)
19. (canceled)
20. A system for monitoring a glucose concentration, the system
comprising: a transcutaneous glucose sensor comprising: an ex vivo
portion configured to remain outside of a body of a host; and an in
vivo portion configured to be inserted into the body of the host,
wherein the in vivo portion comprises: an electrode; and a membrane
disposed over at least a portion of the electrode, wherein the
membrane comprises at least one enzyme; wherein the transcutaneous
glucose sensor is configured to generate a signal, wherein the
magnitude of the signal depends upon a glucose concentration
existing at the in vivo portion of the transcutaneous glucose
sensor inserted into the body of the host; and electronics
configured to operably connect to the transcutaneous glucose
sensor, wherein the electronics comprises a memory, wherein the
memory stores information associated with a profile, wherein the
profile is based at least in part on a priori information related
to expected sensitivity changes associated with a length of time
the in vivo portion of the transcutaneous glucose sensor has been
inserted into the body of the host.
21. The system of claim 20, wherein the electronics is configured
to determine a glucose concentration value based at least in part
on the information associated with the profile.
22. The system of claim 21 wherein the electronics is configured to
determine the glucose concentration value solely using information
obtained prior to insertion of the in vivo portion of the
transcutaneous glucose sensor into the body of the host.
23. The system of claim 21, wherein the electronics is configured
to use a conversion function to determine the glucose concentration
value.
24. The system of claim 23, wherein the conversion function is
based at least in part on a predictive relationship between in
vitro sensitivity and in vivo sensitivity.
25. The system of claim 21 wherein the electronics is configured to
use a calibration factor to determine the glucose concentration
value.
26. The system of claim 21, further comprising a temperature sensor
for providing a temperature measurement, wherein the glucose
concentration value is derived at least in part from the
temperature measurement from the temperature sensor.
27. The system of claim 20, wherein the profile accounts for a
break-in of the transcutaneous glucose sensor after the in vivo
portion of the transcutaneous glucose sensor has been inserted into
the body of the host.
28. The system of claim 20, wherein the electronics comprises
sensor electronics.
29. The system of claim 20, wherein the electronics comprises
receiver electronics.
30. The system of claim 20, wherein the electronics comprises
sensor electronics and receiver electronics.
31. The system of claim 20, wherein the expected sensitivity
changes are associated at least in part with a change in one or
more physical properties of an environment surrounding the in vivo
portion of the transcutaneous glucose sensor within the body of the
host.
32. A method of monitoring a glucose concentration, the method
comprising: beginning a sensor session associated with use of a
transcutaneous glucose sensor, wherein the transcutaneous glucose
sensor comprises: an ex vivo portion configured to remain outside
of a body of a host; and an in vivo portion configured to be
inserted within the body of the host, wherein the in vivo portion
comprises: an electrode; and a membrane disposed over at least a
portion of the electrode, wherein the membrane comprises at least
one enzyme; generating sensor data at least in part from a signal
received from the in vivo portion of the transcutaneous glucose
sensor; and calibrating the sensor data based at least in part on a
priori information, wherein the a priori information comprises a
profile associated with a drift in a sensitivity of the in vivo
portion of the transcutaneous glucose sensor over time.
33. The method of claim 32, wherein the a priori information is
based at least in part on expected sensitivity changes associated
with a length of time the transcutaneous glucose sensor has been
inserted within the body of the host.
34. The method of claim 32, wherein the calibrating comprises
applying a conversion function based at least in part on a
predictive relationship between in vitro sensitivity and in vivo
sensitivity.
35. The method of claim 32, wherein the calibrating comprises
applying a calibration factor based at least in part on a
predictive relationship between in vitro sensitivity and in vivo
sensitivity.
36. The method of claim of claim 32, wherein the calibrating is
performed without a need for a reference analyte value obtained
after insertion of in vivo portion of the transcutaneous glucose
sensor into the body of the host.
37. The method of claim 32, wherein the membrane comprises a
plurality of different membrane layers.
38. The method of claim 32, wherein the drift in the sensitivity is
associated at least in part with a change in one or more physical
properties of an environment surrounding the in vivo portion of the
transcutaneous glucose sensor within the body of the host.
39. The method of claim 32 wherein the profile accounts for
break-in of the transcutaneous glucose sensor.
40. A method for monitoring a glucose concentration, the method
comprising: beginning a sensor session associated with use of a
transcutaneous glucose sensor, wherein the transcutaneous glucose
sensor comprises: an ex vivo portion configured to remain outside
of a body of a host; and an in vivo portion configured to be
inserted within the body of the host; generating sensor data
derived at least in part from the transcutaneous glucose sensor;
determining a glucose concentration value based at least in part on
the sensor data and information associated with a drift profile,
wherein the drift profile is associated with a shift over time in
measurement characteristic of the transcutaneous glucose sensor to
the glucose concentration within the body of the host resulting
from the in vivo portion of the transcutaneous glucose sensor being
within the body of the host for a period of time; and displaying
the glucose concentration value.
41. The method of claim 40 wherein the in vivo portion of the
transcutaneous glucose sensor comprises a substantially planar
configuration.
42. The method of claim 40 wherein the drift profile accounts for a
break-in of the transcutaneous glucose sensor after the in vivo
portion of the transcutaneous glucose sensor has been inserted into
the body of the host.
43. The method of claim 40 wherein the drift profile accounts for a
change in sensitivity over time of the in vivo portion of the
transcutaneous glucose sensor to the glucose concentration within
the body of the host.
44. The method of claim 40 wherein the drift profile accounts for a
change in baseline over time associated with the in vivo portion of
the transcutaneous glucose sensor.
45. The method of claim 40 wherein the drift profile accounts for a
change in baseline over time associated with the in vivo portion of
the transcutaneous glucose sensor and a change in sensitivity over
time of the in vivo portion of the transcutaneous glucose sensor to
the glucose concentration within the body of the host.
46. The method of claim 40 wherein the shift over time is an
elapsed time measured from the beginning of the sensor session.
47. The method of claim 40 wherein the shift over time is
associated at least in part with a change in one or more physical
properties of an environment surrounding the in vivo portion of the
transcutaneous glucose sensor within the body of the host.
48. The method of claim 47 wherein the one or more physical
properties of the environment surrounding the in vivo portion of
the transcutaneous glucose sensor within the body of the host is
associated with at least one of: trauma, wound healing, blockage of
a surface of the transcutaneous glucose sensor, inflammation, blood
clotting, or biofouling.
49. The method of claim 40 wherein the shift over time is
associated at least in part with a physical property of the
transcutaneous glucose sensor, wherein the physical property
corresponds to a membrane of the in vivo portion of the
transcutaneous glucose sensor.
50. The method of claim 40 wherein the shift over time is an
elapsed time measured from the insertion of the in vivo portion of
the transcutaneous glucose sensor within the body of the host.
51. A sensor system comprising: a transcutaneous glucose sensor
comprising: an ex vivo portion configured to remain outside of a
body of a host; and an in vivo portion configured to be implanted
within the body of the host, wherein the in vivo portion comprises:
an electrode; and a membrane disposed over at least a portion of
the electrode, wherein the membrane comprises at least one enzyme;
wherein the transcutaneous glucose sensor generates a signal
associated with a glucose concentration within the body of the
host; and electronics configured to receive the signal from the
transcutaneous glucose sensor, wherein the electronics comprises a
memory, wherein the memory stores information associated with an
expected change over time in a relationship between the signal and
the glucose concentration within the body of the host, wherein the
electronics is configured to generate a glucose concentration value
based at least in part on the signal and the information associated
with the expected change over time in the relationship.
52. The sensor system of claim 51 wherein the change over time in
the relationship is associated at least in part with a change in
one or more physical properties of an environment surrounding the
in vivo portion of the transcutaneous glucose sensor within the
body of the host.
53. The sensor system of claim 52, wherein the one or more physical
properties of the environment surrounding the in vivo portion of
the transcutaneous glucose sensor within the body of the host
include trauma, wound healing, blockage of a surface of the
transcutaneous glucose sensor, inflammation, blood clotting, or
biofouling.
54. The sensor system of claim 51 wherein the change over time in
the relationship is associated with the implantation of the in vivo
portion of the transcutaneous glucose sensor within the body of the
host.
55. The sensor system of claim 51 wherein the change over time in
the relationship is over an elapsed time measured from a beginning
of a sensor session after implantation of the in vivo portion of
the transcutaneous glucose sensor within the body of the host.
56. The sensor system of claim 51 wherein the change over time in
the relationship is over an elapsed time measured from the
implantation of the in vivo portion of the transcutaneous glucose
sensor within the body of the host.
57. The sensor system of claim 51 wherein the change over time in
the relationship is associated at least in part with a physical
property of the transcutaneous glucose sensor, wherein the physical
property of the transcutaneous glucose sensor corresponds to
membrane of the in vivo portion of the transcutaneous glucose
sensor.
58. A method for monitoring a glucose concentration, the method
comprising: beginning a sensor session associated with use of a
transcutaneous glucose sensor, wherein the transcutaneous glucose
sensor comprises: an ex vivo portion configured to remain outside
of a body of a host; and an in vivo portion configured to be
inserted within the body of the host; wherein the transcutaneous
glucose sensor is configured to generate a signal; calibrating the
transcutaneous glucose sensor by applying a priori information,
wherein the a priori information comprises an expected relationship
between the signal and a glucose concentration existing within the
body of the host, wherein the relationship changes as a function of
time; generating a glucose concentration value based at least in
part on the calibrating; and displaying the glucose concentration
value.
59. The method of claim 58 wherein the time the relationship
changes is an elapsed time measured from the beginning of the
sensor session.
60. The method of claim 58 wherein the relationship changes as a
function of time is associated at least in part with a change in
one or more physical properties of an environment surrounding the
in vivo portion of the transcutaneous glucose sensor within the
body of the host.
61. The method of claim 60 wherein the one or more physical
properties of the environment surrounding the in vivo portion of
the transcutaneous glucose sensor within the body of the host
include trauma, wound healing, blockage of a surface of the
transcutaneous glucose sensor, inflammation, blood clotting, or
biofouling.
62. The method of claim 58 wherein the relationship changes as a
function of time is associated at least in part with a physical
property of the transcutaneous glucose sensor, wherein the physical
property of the transcutaneous glucose sensor corresponds to a
membrane of the in vivo portion of the transcutaneous glucose
sensor.
63. The system of claim 20 wherein the profile has a first slope
associated with a first time and a second slope associated with a
second time, wherein the first time is different from the second
time, wherein the first slope is different from the second
slope.
64. The method of claim 32 wherein the profile has a first slope
associated with a first time and a second slope associated with a
second time, wherein the first time is different from the second
time, wherein the first slope is different from the second
slope.
65. The method of claim 40 wherein the drift profile has a first
slope associated with a first time and a second slope associated
with a second time, wherein the first time is different from the
second time, wherein the first slope is different from the second
slope.
Description
INCORPORATION BY REFERENCE TO RELATED APPLICATIONS
[0001] Any and all priority claims identified in the Application
Data Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57. This application is a continuation-in
part of U.S. application Ser. No. 17/078,609, filed Oct. 23, 2020,
and is a continuation-in-part of U.S. application Ser. No.
17/082,627, filed Oct. 28, 2020. The disclosures of each of the
abovementioned applications is hereby expressly incorporated by
reference in its entirety and is hereby expressly made a portion of
this application.
FIELD OF THE INVENTION
[0002] The preferred embodiments relate generally to systems and
methods for measuring an analyte in a host.
BACKGROUND OF THE INVENTION
[0003] In today's medical practice, analyte levels in patient
biological samples (e.g., fluids, tissues and the like collected
from patients) are routinely measured during the process of
diagnosing, monitoring and/or prognosticating a patient's medical
status. For example, a basic metabolic panel (e.g., BMP or chem.-7)
measures sodium, potassium, chloride, bicarbonate, blood urea
nitrogen (BUN), creatinine and glucose. Bodily sample analyte tests
are routinely conducted in a variety of medical settings (e.g.,
doctor's office, clinic, hospital, by medical personnel) and in the
home by the host and/or a caretaker. For example, some medical
conditions require frequent testing of blood analyte levels. For
example, diabetes mellitus, 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),
is one exemplary medical condition, wherein bodily fluid samples
(e.g., blood, interstitial fluid) are routinely tested, in order to
ascertain the patient's (e.g., host's) glucose status, often by the
host or a caretaker. In the diabetic state, the victim suffers from
high blood sugar, which can cause an array of physiological
derangements associated with the deterioration of small blood
vessels, for example, kidney failure, skin ulcers, or bleeding into
the vitreous of the eye. A hypoglycemic reaction (low blood sugar)
can 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 person admitted to a hospital for certain
conditions (with or without diabetes) is tested for blood sugar
level by a single point blood glucose meter, which typically
requires uncomfortable finger pricking methods or blood draws and
can produce a burden on the hospital staff during a patient's
hospital stay. Due to the lack of convenience, blood sugar glucose
levels are generally measured as little as once per day or up to
once per hour. Unfortunately, such time intervals are so far spread
apart that hyperglycemic or hypoglycemic conditions unknowingly
occur, incurring dangerous side effects. It is not only unlikely
that a single point value will not catch some hyperglycemic or
hypoglycemic conditions, it is also likely that the trend
(direction) of the blood glucose value is unknown based on
conventional methods. This inhibits the ability to make educated
insulin therapy decisions.
[0005] A variety of sensors are known that use an electrochemical
cell to provide output signals by which the presence or absence of
an analyte, such as glucose, in a sample can be determined. For
example, in an electrochemical cell, an analyte (or a species
derived from it) that is electro-active generates a detectable
signal at an electrode, and this signal can be used to detect or
measure the presence and/or amount within a biological sample. In
some conventional sensors, an enzyme is provided that reacts with
the analyte to be measured, and the byproduct of the reaction is
qualified or quantified at the electrode. An enzyme has the
advantage that it can be very specific to an analyte and also, when
the analyte itself is not sufficiently electro-active, can be used
to interact with the analyte to generate another species which is
electro-active and to which the sensor can produce a desired
output. In one conventional amperometric glucose oxidase-based
glucose sensor, immobilized glucose oxidase catalyses the oxidation
of glucose to form hydrogen peroxide, which is then quantified by
amperometric measurement (for example, change in electrical
current) through a polarized electrode.
SUMMARY OF THE INVENTION
[0006] In a first aspect, an integrated sensor system is provided
for measuring an analyte in a sample of a host and for fluid
infusion into the host, comprising: an analyte sensor configured
and arranged for measuring an analyte concentration in a biological
sample of a circulatory system of a host; a vascular access device;
tubing assembly comprising tubing; and a flow control device
configured to regulate exposure of the analyte sensor to a
biological sample and to a reference solution according to a flow
profile, wherein the flow control device comprises a valve, and
wherein the valve is configured and arranged with a gravity flow
position and a controlled flow position.
[0007] In an embodiment of the first aspect, the system is
configured such that the analyte sensor is flushed by the reference
solution when the valve is in the gravity flow position.
[0008] In an embodiment of the first aspect, the gravity flow
position comprises a first flow rate of the solution, wherein the
controlled flow position comprises a second flow rate of the
solution, and wherein a ratio of the first flow rate to the second
flow rate is at least about 10:1.
[0009] In an embodiment of the first aspect, the gravity flow
position has a flow rate of at least about 600 ml/hr.
[0010] In an embodiment of the first aspect, the controlled flow
position has a flow rate of from about 0.5 ml/hr to about 4.0
ml/hour.
[0011] In an embodiment of the first aspect, the valve is
configured and arranged to receive the tubing in a substantially
linear configuration.
[0012] In an embodiment of the first aspect, the valve and the
tubing assembly are configured and arranged such that the tubing is
in a stretched state after installation of the tubing in the
valve.
[0013] In an embodiment of the first aspect, valve is configured
and arranged such that the tubing is substantially linear in the
gravity flow position and the tubing is substantially non-linear in
the controlled flow position.
[0014] In an embodiment of the first aspect, the valve is
configured and arranged to preclude tubing installation when the
valve is in the controlled flow position.
[0015] In an embodiment of the first aspect, the valve is
configured and arranged to receive the tubing assembly in only one
orientation.
[0016] In an embodiment of the first aspect, the valve and tubing
assembly are configured and arranged to releasably interlock such
that a portion of the valve mechanically interlocks with a portion
of the tubing assembly.
[0017] In an embodiment of the first aspect, the vascular access
device and the tubing assembly are configured and arranged to
substantially preclude rotational movement between the vascular
access device and the tubing assembly when engaged.
[0018] In an embodiment of the first aspect, the system further
comprises a free-flow mitigation device.
[0019] In an embodiment of the first aspect, the free-flow
mitigation device comprises a spring clip occluder located on the
tubing assembly.
[0020] In an embodiment of the first aspect, the system is
configured for electronic control of the free-flow mitigation
device.
[0021] In an embodiment of the first aspect, the system further
comprises an electronic solenoid associated with the flow control
device, wherein the electronic solenoid provides electronic control
of the free-flow mitigation device.
[0022] In an embodiment of the first aspect, the system is
configured and arranged such that the free-flow mitigation device
precludes flow responsive to at least one of power removal, loss to
the system, and loss to the flow control device.
[0023] In an embodiment of the first aspect, the system is
configured and arranged such that the free-flow mitigation device
is controlled at least in part by the flow profile.
[0024] In an embodiment of the first aspect, the system further
comprises an intravenous bag containing a reference solution,
wherein the reference solution has a known analyte
concentration.
[0025] In an embodiment of the first aspect, the analyte sensor is
configured to measure at least one analyte selected from the group
consisting of albumin, alkaline phosphatase, alanine transaminase,
aspartate aminotransferase, bilirubin, blood urea nitrogen,
calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0026] In a second aspect, a system configured to measure at least
one analyte in a host is provided, the system comprising: a
vascular access device comprising a first portion configured for
insertion into a host and a second portion configured to remain
outside the host after insertion of the first portion; at least one
analyte sensor located within the second portion of the vascular
access device, such that the at least one analyte sensor is exposed
to a biological sample when the biological sample is drawn back by
a distance of about 40 mm or less into the vascular access device,
when the vascular access device is in fluid communication with a
circulatory system of the host; and a flow control device
configured to regulate exposure of the at least one analyte sensor
to a biological sample and to a reference solution according to a
flow profile.
[0027] In an embodiment of the second aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 300 .mu.l or less of the biological sample is drawn back.
[0028] In an embodiment of the second aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 200 .mu.l or less of the biological sample is drawn back.
[0029] In an embodiment of the second aspect, the vascular access
device comprises a catheter.
[0030] In an embodiment of the second aspect, the second portion
comprises a connecting end of the catheter, wherein the connecting
end is configured for connection to tubing.
[0031] In an embodiment of the second aspect, the vascular access
device is a catheter, and wherein the catheter is 22 gauge or
smaller.
[0032] In an embodiment of the second aspect, the second portion
comprises a fluid coupler, wherein the fluid coupler is configured
to releasably mate with the catheter.
[0033] In an embodiment of the second aspect, the at least one
sensor is incorporated into the second portion.
[0034] In an embodiment of the second aspect, the at least one
sensor is located on an inner surface of the second portion.
[0035] In an embodiment of the second aspect, the at least one
sensor is disposed within a lumen of the second portion.
[0036] In an embodiment of the second aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
parallel to a longitudinal axis of the second portion.
[0037] In an embodiment of the second aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
perpendicular to a longitudinal axis of the second portion.
[0038] In an embodiment of the second aspect, the at least one
sensor comprises an exposed electroactive surface area with a
dimension substantially equal to a width of a lumen of the second
portion.
[0039] In an embodiment of the second aspect, the exposed
electroactive surface area intersects the lumen of the second
portion.
[0040] In an embodiment of the second aspect, the second portion is
configured to provide identification information associated with
the flow profile.
[0041] In an embodiment of the second aspect, the system is
configured to program the flow profile of the flow control device
in response to an automatic receipt of the identification
information.
[0042] In an embodiment of the second aspect, the identification
information is provided by a mechanical structure of the second
portion.
[0043] In an embodiment of the second aspect, the identification
information is provided by electronics of the second portion.
[0044] In an embodiment of the second aspect, the vascular access
device comprises at least two lumens, and wherein the system is
configured and arranged to infuse a fluid into a first lumen of the
vascular access device, and wherein the system is configured and
arranged to draw back a biological sample into a second lumen of
the vascular access device.
[0045] In an embodiment of the second aspect, the at least one
analyte sensor is configured to measure an analyte selected from
the group consisting of albumin, alkaline phosphatase, alanine
transaminase, aspartate aminotransferase, bilirubin, blood urea
nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0046] In an embodiment of the second aspect, the system comprises
at least three analyte sensors located within the second portion of
the vascular access device, wherein the three sensors in
combination are configured to measure at least three analytes
selected from the group consisting of albumin, alkaline
phosphatase, alanine transaminase, aspartate aminotransferase,
bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,
creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit,
lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus,
potassium, sodium, total protein, uric acid, a metabolic marker and
a drug.
[0047] In an embodiment of the second aspect, the system comprises
at least eight analyte sensors located within the second portion of
the vascular access device, wherein the three sensors in
combination are configured to measure at least eight analytes
selected from the group consisting of albumin, alkaline
phosphatase, alanine transaminase, aspartate aminotransferase,
bilirubin, blood urea nitrogen, calcium, carbon dioxide, chloride,
creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit,
lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus,
potassium, sodium, total protein, uric acid, a metabolic marker and
a drug.
[0048] In an embodiment of the second aspect, a lumen of the second
portion is wider than a lumen of the first portion.
[0049] In a third aspect, a system configured to measure at least
one analyte in a host is provided, the system comprising: a
catheter comprising a first portion configured for insertion into a
host and a second portion configured to remain outside the host
after insertion of the first portion; and at least one analyte
sensor located within the second portion of the catheter, such that
the at least one analyte sensor is exposed to a biological sample
when the biological sample is drawn back into the catheter to a
distance of about 40 mm or less, when the catheter is in fluid
communication with a circulatory system of the host.
[0050] In an embodiment of the third aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 300 .mu.l or less of the biological sample is drawn back.
[0051] In an embodiment of the third aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 200 .mu.l or less of the biological sample is drawn back.
[0052] In an embodiment of the third aspect, the catheter is 22
gauge or smaller.
[0053] In an embodiment of the third aspect, the second portion
comprises a fluid coupler, wherein the fluid coupler is configured
to releasably mate with the catheter.
[0054] In an embodiment of the third aspect, the at least one
sensor is incorporated into the second portion.
[0055] In an embodiment of the third aspect, the at least one
sensor is located on an inner surface of the second portion.
[0056] In an embodiment of the third aspect, the at least one
sensor is disposed within a lumen of the second portion.
[0057] In an embodiment of the third aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
parallel to a longitudinal axis of the second portion.
[0058] In an embodiment of the third aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
perpendicular to a longitudinal axis of the second portion.
[0059] In an embodiment of the third aspect, the at least one
sensor comprises an exposed electroactive surface area with a
dimension substantially equal to a width of a lumen of the second
portion.
[0060] In an embodiment of the third aspect, the exposed
electroactive surface area intersects the lumen of the second
portion.
[0061] In an embodiment of the third aspect, the second portion is
configured to provide identification information associated with a
flow profile.
[0062] In an embodiment of the third aspect, the system is
configured to program the flow profile of the flow control device
in response to an automatic receipt of the identification
information.
[0063] In an embodiment of the third aspect, the identification
information is provided by a mechanical structure of the
catheter.
[0064] In an embodiment of the third aspect, the identification
information is provided by electronics associated with the
catheter.
[0065] In an embodiment of the third aspect, the catheter comprises
at least two lumens, and wherein the system is configured and
arranged to infuse a fluid into a first lumen of the catheter, and
wherein the system is configured and arranged draw back a
biological sample into a second lumen of the catheter.
[0066] In an embodiment of the third aspect, the at least one
analyte sensor is configured to measure an analyte selected from
the group consisting of albumin, alkaline phosphatase, alanine
transaminase, aspartate aminotransferase, bilirubin, blood urea
nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0067] In an embodiment of the third aspect, the system comprises
at least three analyte sensors located within the second portion of
the catheter, wherein the three sensors in combination are
configured to measure at least three analytes selected from the
group consisting of albumin, alkaline phosphatase, alanine
transaminase, aspartate aminotransferase, bilirubin, blood urea
nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0068] In an embodiment of the third aspect, the system comprises
at least eight analyte sensors located within the second portion of
the catheter, wherein the eight sensors in combination are
configured to measure at least eight analytes selected from the
group consisting of albumin, alkaline phosphatase, alanine
transaminase, aspartate aminotransferase, bilirubin, blood urea
nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0069] In an embodiment of the third aspect, the system further
comprises a flow control device configured to regulate exposure of
the at least one sensor to a biological sample and to a solution
according to a flow profile.
[0070] In an embodiment of the third aspect, a lumen of the second
portion is wider than a lumen of the first portion.
[0071] In a fourth aspect, a system configured to measure at least
one analyte in a biological sample of the host is provided, the
system comprising: a fluid coupler comprising a first end and a
second end, wherein the first end is configured to releasably mate
with a connecting end of a catheter, and wherein the second end is
configured to releasably mate with a tubing assembly; and at least
one analyte sensor located within the fluid coupler such that when
the fluid coupler is mated to a catheter inserted into a
circulatory system of a host, the at least one analyte sensor is
exposed to a biological sample when the biological sample is drawn
back into the catheter to a distance of about 40 mm or less.
[0072] In an embodiment of the fourth aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 300 .mu.l or less of the biological sample is drawn back.
[0073] In an embodiment of the fourth aspect, the at least one
analyte sensor is exposed to the biological sample when a volume of
about 200 .mu.l or less of the biological sample is drawn back.
[0074] In an embodiment of the fourth aspect, the at least one
analyte sensor is incorporated into the fluid coupler.
[0075] In an embodiment of the fourth aspect, the at least one
analyte sensor is located on an inner surface of the fluid
coupler.
[0076] In an embodiment of the fourth aspect, the at least one
analyte sensor is disposed within a lumen of the fluid coupler.
[0077] In an embodiment of the fourth aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
parallel to a longitudinal axis of the fluid coupler.
[0078] In an embodiment of the fourth aspect, at least a portion of
the at least one sensor is disposed in an orientation substantially
perpendicular to a longitudinal axis of the fluid coupler.
[0079] In an embodiment of the fourth aspect, the at least one
sensor comprises an exposed electroactive surface area with a
dimension substantially equal to a width of a lumen of the fluid
coupler.
[0080] In an embodiment of the fourth aspect, the exposed
electroactive surface area intersects the lumen of the fluid
coupler.
[0081] In an embodiment of the fourth aspect, the fluid coupler is
configured to provide identification information associated with a
flow profile.
[0082] In an embodiment of the fourth aspect, the system is
configured to program the flow profile of the flow control device
in response to an automatic receipt of the identification
information.
[0083] In an embodiment of the fourth aspect, the identification
information is provided by a mechanical structure of the fluid
coupler.
[0084] In an embodiment of the fourth aspect, the identification
information is provided by electronics associated with the fluid
coupler.
[0085] In an embodiment of the fourth aspect, the fluid coupler
comprises at least two lumens, and wherein the system is configured
and arranged to infuse a fluid into a first lumen of the fluid
coupler, and wherein the system is configured and arranged draw
back a biological sample into a second lumen of the fluid
coupler.
[0086] In an embodiment of the fourth aspect, the at least one
analyte sensor is configured to measure an analyte selected from
the group consisting of albumin, alkaline phosphatase, alanine
transaminase, aspartate aminotransferase, bilirubin, blood urea
nitrogen, calcium, carbon dioxide, chloride, creatinine, glucose,
gamma-glutamyl transpeptidase, hematocrit, lactate, lactate
dehydrogenase, magnesium, oxygen, pH, phosphorus, potassium,
sodium, total protein, uric acid, a metabolic marker and a
drug.
[0087] In an embodiment of the fourth aspect, the system comprises
at least three analyte sensors located within the fluid coupler,
wherein the three sensors in combination are configured to measure
at least three analytes selected from the group consisting of
albumin, alkaline phosphatase, alanine transaminase, aspartate
aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon
dioxide, chloride, creatinine, glucose, gamma-glutamyl
transpeptidase, hematocrit, lactate, lactate dehydrogenase,
magnesium, oxygen, pH, phosphorus, potassium, sodium, total
protein, uric acid, a metabolic marker and a drug.
[0088] In an embodiment of the fourth aspect, the system comprises
at least eight analyte sensors located within the fluid coupler,
wherein the three sensors in combination are configured to measure
at least eight analytes selected from the group consisting of
albumin, alkaline phosphatase, alanine transaminase, aspartate
aminotransferase, bilirubin, blood urea nitrogen, calcium, carbon
dioxide, chloride, creatinine, glucose, gamma-glutamyl
transpeptidase, hematocrit, lactate, lactate dehydrogenase,
magnesium, oxygen, pH, phosphorus, potassium, sodium, total
protein, uric acid, a metabolic marker and a drug.
[0089] In an embodiment of the fourth aspect, the system further
comprises a catheter.
[0090] In an embodiment of the fourth aspect, the system further
comprises a flow control device configured to regulate exposure of
the at least one sensor to a biological sample and to a solution
according to a flow profile.
[0091] In a fifth aspect, a method for evaluating a change in a
sensitivity of an analyte sensor over a predetermined time period
is provided, the method comprising: receiving sensor data from an
analyte sensor, wherein the sensor data comprises one or more
sensor analyte values measured in a biological sample of a host;
intermittently calculating a sensitivity of the analyte sensor
based at least in part on reference analyte data; and evaluating a
change in sensitivity by evaluating a plurality of time-spaced
sensitivity calculations over a predetermined time period.
[0092] In an embodiment of the fifth aspect, the predetermined time
period is less than or equal to about 30 minutes.
[0093] In an embodiment of the fifth aspect, the predetermined time
period is less than or equal to about 20 minutes.
[0094] In an embodiment of the fifth aspect, the predetermined time
period is less than or equal to about 10 minutes.
[0095] In an embodiment of the fifth aspect, the step of evaluating
a change in sensitivity comprises evaluating at least two
sensitivity measurements during the predetermined time period.
[0096] In an embodiment of the fifth aspect, the method further
comprises averaging and/or filtering the at least two sensitivity
measurements prior to the step of evaluating the at least two
sensitivity measurements.
[0097] In an embodiment of the fifth aspect, the step of evaluating
a change in sensitivity comprises comparing the change in
sensitivity with one or more criteria.
[0098] In an embodiment of the fifth aspect, the method further
comprises using a most recent sensitivity calculation evaluated to
calibrate the analyte sensor when the change in sensitivity meets
one or more criteria.
[0099] In an embodiment of the fifth aspect, the method further
comprises not using a most recent sensitivity calculation evaluated
to calibrate the analyte sensor when the change in sensitivity does
not meet one or more criteria.
[0100] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor
comprises intermittently receiving a reference analyte value.
[0101] In an embodiment of the fifth aspect, the step of
intermittently receiving a reference analyte value comprises
periodically receiving a measured analyte concentration from a
reference analyte solution.
[0102] In an embodiment of the fifth aspect, the step of
intermittently receiving a reference analyte value comprises
receiving a reference analyte value obtained from an in vitro
analyte monitor.
[0103] In an embodiment of the fifth aspect, the step of evaluating
a sensitivity is iteratively performed on the plurality of
time-spaced sensitivity calculations over the predetermined time
period.
[0104] In an embodiment of the fifth aspect, the predetermined time
period is at least about 30 minutes.
[0105] In an embodiment of the fifth aspect, the predetermined time
period is at least about 60 minutes.
[0106] In an embodiment of the fifth aspect, the predetermined time
period is at least about 120 minutes.
[0107] In an embodiment of the fifth aspect, the step of evaluating
a sensitivity is iteratively performed on the plurality of
time-spaced sensitivity calculations over the predetermined time
period.
[0108] In an embodiment of the fifth aspect, the step of evaluating
a sensitivity comprises evaluating all sensitivity calculations
over a sensor session.
[0109] In an embodiment of the fifth aspect, the step of evaluating
a sensitivity is based at least in part on a priori sensitivity
information.
[0110] In an embodiment of the fifth aspect, the a priori
sensitivity information is an expected profile.
[0111] In an embodiment of the fifth aspect, the a priori
sensitivity information defines a range of acceptable change in
sensitivity.
[0112] In an embodiment of the fifth aspect, the analyte sensor
comprises a first working electrode and a second working electrode,
wherein the first working electrode is configured to provide a
first signal comprising an analyte component and a baseline
component and wherein the second working electrode is configured to
provide a second signal comprising a baseline component without an
analyte component.
[0113] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on the first signal.
[0114] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on the second signal.
[0115] In an embodiment of the fifth aspect, the method further
comprises subtracting the second signal from the first signal to
obtain a subtracted signal, wherein the step of intermittently
calculating a sensitivity of the analyte sensor is based at least
in part on the subtracted signal.
[0116] In an embodiment of the fifth aspect, the analyte sensor is
intermittently exposed to a biological sample and to a reference
solution.
[0117] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on a signal obtained when the analyte sensor
is exposed to a biological sample.
[0118] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on a signal obtained when the analyte sensor
is exposed to a reference solution.
[0119] In an embodiment of the fifth aspect, the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on a signal obtained when the analyte sensor
is exposed to a biological sample and a signal obtained when the
analyte sensor is exposed to a reference solution.
[0120] In a sixth aspect, a system for evaluating a change in a
sensitivity of an analyte sensor over a predetermined time period
is provided, the system comprising: an analyte sensor; and a
computer system, wherein the computer system comprises: an input
module configured to receive sensor analyte data and reference
analyte data, wherein the sensor data comprises one or more sensor
analyte values measured in a biological sample of a host and
wherein the reference data comprises one or more reference analyte
values; and a processor module configured to intermittently
calculate a sensitivity of the analyte sensor based at least in
part on the reference analyte data and to evaluate a change in
sensitivity by evaluating a plurality of time-spaced sensitivity
calculations over a predetermined time period.
[0121] In an embodiment of the sixth aspect, the predetermined time
period is less than or equal to about 30 minutes.
[0122] In an embodiment of the sixth aspect, the predetermined time
period is less than or equal to about 20 minutes.
[0123] In an embodiment of the sixth aspect, the predetermined time
period is less than or equal to about 10 minutes.
[0124] In an embodiment of the sixth aspect, the processor module
is configured to evaluate the change in sensitivity at least in
part by evaluating at least two sensitivity measurements during the
predetermined time period.
[0125] In an embodiment of the sixth aspect, the processor module
is further configured to average and/or filter the at least two
sensitivity measurements prior to evaluating the at least two
sensitivity measurements.
[0126] In an embodiment of the sixth aspect, the processor module
is further configured to compare the change in sensitivity with one
or more criteria.
[0127] In an embodiment of the sixth aspect, the processor module
is further configured to use a most recent sensitivity calculation
evaluated to calibrate the analyte sensor when the change in
sensitivity meets one or more criteria.
[0128] In an embodiment of the sixth aspect, the processor module
is further configured to not use a most recent sensitivity
calculation evaluated to calibrate the analyte sensor when the
change in sensitivity does not meet one or more criteria.
[0129] In an embodiment of the sixth aspect, the predetermined time
period is at least about 30 minutes.
[0130] In an embodiment of the sixth aspect, the predetermined time
period is at least about 60 minutes.
[0131] In an embodiment of the sixth aspect, the predetermined time
period is at least about 120 minutes.
[0132] In an embodiment of the sixth aspect, the processor module
is configured to iteratively evaluate a sensitivity of the
plurality of time-spaced sensitivity calculations over the
predetermined time period.
[0133] In an embodiment of the sixth aspect, the processor module
is configured to evaluate all sensitivity calculations over a
sensor session.
[0134] In an embodiment of the sixth aspect, the processor module
is configured to evaluate a sensitivity based at least in part on a
priori sensitivity information.
[0135] In an embodiment of the sixth aspect, the a priori
sensitivity information is an expected profile.
[0136] In an embodiment of the sixth aspect, the a priori
sensitivity information defines a range of acceptable change in
sensitivity.
[0137] In an embodiment of the sixth aspect, the analyte sensor
data comprises a first signal comprising an analyte component and a
baseline component and a second signal comprising a baseline
component without an analyte component.
[0138] In an embodiment of the sixth aspect, the processor module
is configured to calculate a sensitivity of the analyte sensor
based at least in part on the first signal.
[0139] In an embodiment of the sixth aspect, the processor module
is configured to calculate a sensitivity of the analyte sensor
based at least in part on the second signal.
[0140] In an embodiment of the sixth aspect, the processor module
is further configured to calculate a sensitivity of the analyte
sensor based at least in part on a subtracted signal, wherein the
subtracted signal comprises the second signal subtracted from the
first signal.
[0141] In an embodiment of the sixth aspect, the system further
comprises a flow control device configured to intermittently expose
the sensor to the biological sample and to a reference
solution.
[0142] In an embodiment of the sixth aspect, the processor module
is configured to intermittently calculate a sensitivity of the
analyte sensor based at least in part on a signal obtained when the
analyte sensor is exposed to the biological sample.
[0143] In an embodiment of the sixth aspect, the processor module
is configured to intermittently calculate a sensitivity of the
analyte sensor based at least in part on a signal obtained when the
analyte sensor is exposed to the reference solution.
[0144] In an embodiment of the sixth aspect, the processor module
is configured to intermittently calculate a sensitivity of the
analyte sensor based on a signal obtained when the analyte sensor
is exposed to the biological sample and a signal obtained when the
analyte sensor is exposed to the reference solution.
[0145] In a seventh aspect, a method for performing a diagnostic of
an analyte sensor system is provided, comprising: providing a
sensor system comprising an analyte sensor and a flow control
device configured to intermittently expose the analyte sensor to a
biological sample and an infusion solution, wherein the analyte
sensor comprises: a first working electrode configured to provide a
first signal comprising an analyte component and a baseline
component; and a second working electrode configured to provide a
second signal comprising a baseline component substantially without
an analyte component; and evaluating the sensor system based at
least in part on the second signal.
[0146] In an embodiment of the seventh aspect, the second signal
comprises a signal waveform, and wherein the step of evaluating the
sensor system comprises evaluating the signal waveform for at least
one of an expected shape and a pattern when the analyte sensor is
exposed to at least one of the biological sample and the infusion
solution.
[0147] In an embodiment of the seventh aspect, the step of
evaluating the signal waveform comprises evaluating at least one of
a similarity and a correlation between the signal waveform and a
waveform template.
[0148] In an embodiment of the seventh aspect, the waveform
template is based at least in part on a priori information.
[0149] In an embodiment of the seventh aspect, the waveform
template is based at least in part on a signal waveform measured by
the sensor system.
[0150] In an embodiment of the seventh aspect, the step of
evaluating at least one of a similarity and a correlation of the
signal waveform to a waveform template comprises performing a
correlation waveform analysis.
[0151] In an embodiment of the seventh aspect, the method further
comprises updating the waveform template when at least one of the
similarity and the correlation between the signal waveform and the
waveform template meets one or more criteria.
[0152] In an embodiment of the seventh aspect, the method further
comprises detecting a level of interferent in the biological
sample, wherein the waveform template is updated when the level of
interferent meets one or more criteria.
[0153] In an embodiment of the seventh aspect, the step of
evaluating the signal waveform comprises evaluating a monotonicity
of the signal waveform.
[0154] In an embodiment of the seventh aspect, the step of
evaluating a monotonicity of the signal waveform comprises
performing a correlation waveform analysis of the signal waveform
with the waveform template.
[0155] In an embodiment of the seventh aspect, the step of
evaluating a monotonicity of the signal waveform comprises
performing a time-series analysis.
[0156] In an embodiment of the seventh aspect, the step of
evaluating the sensor system comprises detecting an interferent by
evaluating at least one of an amplitude, a change in amplitude, a
signal waveform, and a change in a signal waveform of the second
signal when the sensor is exposed to the biological sample.
[0157] In an embodiment of the seventh aspect, the step of
detecting an interferent is further based at least in part on a
calibrated analyte value.
[0158] In an embodiment of the seventh aspect, the method further
comprises controlling a display of the sensor system based at least
in part on a level of interferent detected on the second
signal.
[0159] In an embodiment of the seventh aspect, the method further
comprises processing the first signal and the second signal to
obtain a subtracted signal, wherein the step of processing is based
at least in part a level of interferent of the sensor system.
[0160] In an embodiment of the seventh aspect, the method further
comprises determining a level of reliability of the sensor system
by comparing at least one of an amplitude, a change in amplitude, a
signal waveform, and a change in a signal waveform of the second
signal to one or more criteria.
[0161] In an embodiment of the seventh aspect, the method further
comprises controlling a display of the sensor system based at least
in part on the level of reliability of the sensor system.
[0162] In an embodiment of the seventh aspect, the step of
evaluating comprises determining a success of a biological sample
draw-back from a host's circulatory system to the analyte
sensor.
[0163] In an embodiment of the seventh aspect, the method further
comprises displaying an analyte value measured during the
biological sample draw-back in response to a determination of a
successful biological sample draw-back.
[0164] In an embodiment of the seventh aspect, the step of
evaluating comprises determining a success of infusing the infusion
solution such that the biological sample is washed from the
sensor.
[0165] In an embodiment of the seventh aspect, the step of
determining a success of infusing comprises displaying an analyte
value measured in the biological sample after infusing the infusion
solution in response to a determination of a successful
infusion.
[0166] In an eighth aspect, a system for performing a diagnostic of
an analyte sensor system is provided, comprising: an analyte sensor
system comprising a sensor, wherein the analyte sensor comprises a
first working electrode configured to provide a first signal
comprising an analyte component and a baseline component and a
second working electrode configured to provide a second signal
comprising a baseline component substantially without an analyte
component; a flow control device configured to intermittently
expose the analyte sensor to a biological sample and an infusion
solution; and a processor module configured to evaluate the analyte
sensor system based at least in part on the second signal.
[0167] In an embodiment of the eighth aspect, the second signal
comprises a signal waveform, and wherein the processor module is
configured to evaluate the signal waveform for at least one of an
expected shape and a pattern when the analyte sensor is exposed to
at least one of the biological sample and the infusion
solution.
[0168] In an embodiment of the eighth aspect, the processor module
is configured to evaluate the signal waveform by evaluating at
least one of a similarity and a correlation between the signal
waveform and a waveform template.
[0169] In an embodiment of the eighth aspect, the waveform template
is based at least in part on a priori information.
[0170] In an embodiment of the eighth aspect, the waveform template
is based at least in part on a signal waveform measured by the
analyte sensor system.
[0171] In an embodiment of the eighth aspect, the processor module
is configured to evaluate at least one of a similarity and a
correlation between the signal waveform and the waveform template
by performing a correlation waveform analysis.
[0172] In an embodiment of the eighth aspect, the processor module
is further configured to update the waveform template when at least
one of a similarity and a correlation between the signal waveform
and the waveform template meets one or more criteria.
[0173] In an embodiment of the eighth aspect, the processor module
is configured to detect a level of an interferent in the biological
sample, and wherein the processor module is further configured to
update the waveform template when the level of the interferent
meets one or more criteria.
[0174] In an embodiment of the eighth aspect, the processor module
is configured to evaluate the signal waveform by evaluating a
monotonicity of the signal waveform.
[0175] In an embodiment of the eighth aspect, the processor module
is configured to evaluate a monotonicity at least in part by
performing a correlation waveform analysis of the signal waveform
with a waveform template.
[0176] In an embodiment of the eighth aspect, the processor module
is configured evaluate a monotonicity at least in part by
performing a time-series analysis.
[0177] In an embodiment of the eighth aspect, the processor module
is configured to detect an interferent at least in part by
evaluating at least one of an amplitude, a change in amplitude, a
signal waveform, and a change in a signal waveform of the second
signal when the sensor is exposed to a biological sample.
[0178] In an embodiment of the eighth aspect, the processor module
is configured to detect an interferent at least in part by
evaluating a calibrated analyte value with one or more
criteria.
[0179] In an embodiment of the eighth aspect, the one or more
criteria are based on physiological feasibility.
[0180] In an embodiment of the eighth aspect, the processor module
is configured to control a display of the analyte sensor system
based at least in part on a level of an interferent detected on the
second signal.
[0181] In an embodiment of the eighth aspect, the processor module
is further configured to process the first signal and the second
signal to obtain a subtracted signal based at least in part on a
level of an interferent of the sensor system.
[0182] In an embodiment of the eighth aspect, the processor module
is configured evaluate a level of reliability of the sensor system
at least in part by comparing at least one of an amplitude, a
change in amplitude, a signal waveform, and a change in a signal
waveform of the second signal to one or more criteria.
[0183] In an embodiment of the eighth aspect, the processor module
is configured to control a display of the sensor system based at
least in part on a level of reliability of the sensor system.
[0184] In an embodiment of the eighth aspect, processor module is
further configured determine a success of drawing-back of a
biological sample from a host's circulatory system to the analyte
sensor, based at least in part on the evaluation of the analyte
sensor system.
[0185] In an embodiment of the eighth aspect, the processor module
is configured to display an analyte value measured during the
biological sample draw-back, in response to a determination of a
successful draw-back of the biological sample.
[0186] In an embodiment of the eighth aspect, the processor module
is further configured to determine a success of infusing the
infusion solution such that the biological sample is washed from
the sensor.
[0187] In an embodiment of the eighth aspect, the processor module
is configured to display an analyte value measured in the
biological sample after infusing the infusion solution, in response
to a determination of a successful infusion.
[0188] In a ninth aspect, a method for determining a stability of
an analyte sensor is provided, the method comprising: exposing an
analyte sensor to a biological sample, wherein the analyte sensor
comprises a first working electrode that measures an analyte
component and a baseline component and a second working electrode
that measures a baseline component substantially without an analyte
component; receiving sensor data from the analyte sensor, wherein
the sensor data comprises first sensor data associated with the
first working electrode and second sensor data associated with the
second working electrode; and determining a stability of the
analyte sensor based at least in part on the second sensor
data.
[0189] In an embodiment of the ninth aspect, the second sensor data
comprises a plurality of time spaced data points, and wherein the
step of determining a stability of the analyte sensor comprises
evaluating a change in amplitude of two or more of the plurality of
time spaced data points.
[0190] In an embodiment of the ninth aspect, the step of exposing
the analyte sensor to a biological sample comprises intermittently
exposing the analyte sensor to a biological sample and to an
infusion solution.
[0191] In an embodiment of the ninth aspect, the step of evaluating
comprises comparing a plurality of time spaced points measured when
the analyte sensor is exposed to the biological sample.
[0192] In an embodiment of the ninth aspect, the step of evaluating
comprises comparing a first point measured when the analyte sensor
is exposed to the biological sample to a second point measured when
the analyte sensor is exposed to the infusion solution.
[0193] In an embodiment of the ninth aspect, the step of evaluating
comprises evaluating transient information of the second sensor
data during a step change from exposure of the sensor to the
infusion solution to exposure of the sensor to the biological
sample.
[0194] In an embodiment of the ninth aspect, the method further
comprises determining a predetermined level of stability when a
change in an amplitude of the second sensor data meets one or more
criteria.
[0195] In an embodiment of the ninth aspect, the method further
comprises controlling a display associated with the analyte sensor
system in response to the determination of the predetermined level
of stability.
[0196] In an embodiment of the ninth aspect, the step of
controlling a display comprises providing at least one of a numeric
estimated analyte value, a directional trend of analyte
concentration, and a graphical representation of a plurality of
estimated analyte values.
[0197] In an embodiment of the ninth aspect, the step of
controlling a display comprises requesting reference analyte
data.
[0198] In an embodiment of the ninth aspect, the step of
determining a stability of the analyte sensor is performed during a
predetermined time period.
[0199] In an embodiment of the ninth aspect, the step of
determining a stability of the analyte sensor is performed after a
predetermined time period.
[0200] In an embodiment of the ninth aspect, the method further
comprises repeating the step of determining a stability, wherein
the step is conducted after a system re-start.
[0201] In an embodiment of the ninth aspect, the analyte sensor is
a glucose sensor.
[0202] In a tenth aspect, a system for determining a stability of
an analyte sensor is provided, the system comprising: an analyte
sensor; and a computer system, the computer system comprising: an
input module operatively connected to the analyte sensor and
configured to receive sensor data from an analyte sensor, wherein
the analyte sensor comprises a first working electrode configured
to provide first sensor data comprising an analyte component and a
baseline component and a second working electrode configured to
provide second sensor data comprising a baseline component
substantially without an analyte component; and a processor module
configured to determine a stability of the analyte sensor based at
least in part on the second sensor data.
[0203] In an embodiment of the tenth aspect, the processor module
is configured to determine a stability of the analyte sensor at
least in part by evaluating a change in amplitude of a plurality of
time spaced points from the second sensor data.
[0204] In an embodiment of the tenth aspect, the system further
comprises a flow control device configured and arranged to
intermittently expose the analyte sensor to a biological sample and
to an infusion solution.
[0205] In an embodiment of the tenth aspect, the processor module
is configured to evaluate the change in amplitude at least in part
by comparing a plurality of time spaced points from the second
sensor data measured when the analyte sensor is exposed to the
biological sample.
[0206] In an embodiment of the tenth aspect, the processor module
is configured to evaluate the change in amplitude at least in part
by comparing a first point measured when the analyte sensor is
exposed to the biological sample to a second point measured when
the analyte sensor is exposed to the infusion solution.
[0207] In an embodiment of the tenth aspect, the processor module
is configured to evaluate the change in amplitude at least in part
by evaluating transient information of the second sensor data
during a step change from exposure of the sensor to the infusion
solution to exposure of the sensor to the biological sample.
[0208] In an embodiment of the tenth aspect, the processor module
is configured to determine a level of stability when a change in
amplitude of a plurality of time spaced points from the second
sensor data meets one or more criteria.
[0209] In an embodiment of the tenth aspect, the processor module
is configured to control a display of calibrated sensor based at
least in part on the level of stability.
[0210] In an embodiment of the tenth aspect, the calibrated sensor
data comprises at least one of a numeric estimated analyte value, a
directional trend of analyte concentration, and a graphical
representation of a plurality of estimated analyte values.
[0211] In an embodiment of the tenth aspect, the processor module
is configured to request reference analyte data based at least in
part on the level of stability.
[0212] In an embodiment of the tenth aspect, the processor module
is further configured to determine a stability of the analyte
sensor during a predetermined time period.
[0213] In an embodiment of the tenth aspect, processor module is
further configured to determine a stability of the analyte sensor
after a predetermined time period.
[0214] In an embodiment of the tenth aspect, the analyte sensor is
a glucose sensor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0215] FIG. 1A is a perspective view of one embodiment of an
analyte sensor system, including a vascular access device (e.g., a
catheter), a sensor, a fluid connector, and a protective
sheath.
[0216] FIG. 1B is a side view of the analyte sensor system of FIG.
1A, showing the protective sheath removed.
[0217] FIG. 1C.sub.1 is a close-up cut away view of a portion of
the analyte sensor system of FIG. 1A.
[0218] FIG. 1C.sub.2 is a close-up cut away view of a portion of
the analyte sensor system of FIG. 1A.
[0219] FIG. 1D is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0220] FIG. 1E is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0221] FIG. 1F is a schematic an analyte sensor system in another
embodiment, including a vascular access device, a sensor, a fluid
connector, and a protective sheath.
[0222] FIG. 1G is an exploded view of the analyte sensor system of
FIG. 1F.
[0223] FIG. 1H is a cut-away view of the analyte sensor system of
FIG. 1F.
[0224] FIG. 1J is a magnified view of the encircled portion of the
analyte sensor system of FIG. 1H.
[0225] FIG. 1K is a cut-away view of an analyte sensor system in
another embodiment.
[0226] FIG. 1L is a cut-away view of an analyte sensor system in
another embodiment.
[0227] FIG. 1M is a cut-away view of an analyte sensor system in
another embodiment.
[0228] FIG. 2A is a perspective view of another embodiment of the
analyte sensor system, including a catheter with a sensor
integrally formed thereon.
[0229] FIG. 2B is a perspective view of the analyte sensor system
of FIG. 2A.
[0230] FIG. 2C is a close-up view of a portion of the analyte
sensor system of FIG. 2A in an alternative configuration of an
embodiment having three electrodes disposed on the catheter.
[0231] FIG. 2D is a close-up view of a portion of the analyte
sensor system of FIG. 2A in an alternative configuration of an
embodiment having three electrodes disposed on the catheter.
[0232] FIG. 2E is a close-up view of a portion of the analyte
sensor system of FIG. 2A in an alternative embodiment having two
electrodes disposed on the catheter.
[0233] FIG. 2F is a close-up view of a portion of the analyte
sensor system of FIG. 2A in an alternative embodiment having one
electrode disposed on the catheter.
[0234] FIG. 2G is a cross-section of analyte sensor system in one
embodiment, including a plurality of analyte sensors disposed
within the connector of a catheter.
[0235] FIG. 2H is a cross-section of analyte sensor system in one
embodiment, including a plurality of analyte sensors disposed
within a fluid coupler, such as but not limited to a connector, a
valve, and a Leur lock.
[0236] FIG. 2I is a cross-section of analyte sensor system of FIG.
2H, taken along line 2I-2I.
[0237] FIG. 2J is a cross-section of analyte sensor system of FIG.
2H, taken along line 2I-2I.
[0238] FIG. 2K is a cross-section of analyte sensor system of FIG.
2H, taken along line 2I-2I.
[0239] FIG. 2L is a cross-section of analyte sensor system of FIG.
2H, taken along line 2I-2I.
[0240] FIG. 2M is a side view schematic of an analyte sensor system
in another embodiment, including a plurality of electrodes disposed
in a fluid coupler.
[0241] FIG. 2N is a schematic of an analyte sensor system in yet
another embodiment, including a fluid coupler having a plurality of
lumens, each of which includes an analyte sensor.
[0242] FIG. 2O is a schematic illustrating a method of
manufacturing the analyte sensor system of FIG. 2M, in one
embodiment.
[0243] FIG. 2P is a schematic illustrating a method of
manufacturing the analyte sensor system of FIG. 2M, in another
embodiment.
[0244] FIG. 2Q is a side view schematic of an analyte sensor
system, including a fluid coupler including a plurality of sensor
electrodes disposed therein, in one embodiment.
[0245] FIG. 2R is a cross-sectional schematic of an analyte sensor
system, including a fluid coupler including a plurality of sensor
electrodes disposed therein, in another embodiment.
[0246] FIG. 2S is a side view schematic of an analyte sensor
system, including a fluid coupler including a plurality of sensor
electrodes disposed therein, in still another embodiment.
[0247] FIG. 3A is a perspective view of a first portion of one
embodiment of an analyte sensor.
[0248] FIG. 3B is a perspective view of a second portion of the
analyte sensor of FIG. 3A.
[0249] FIG. 3C is a cross section of the analyte sensor of FIG. 3B,
taken on line C-C.
[0250] FIG. 3D is a cross-sectional schematic view of a sensing
region of a dual-electrode continuous analyte sensor in one
embodiment wherein an active enzyme of an enzyme domain is
positioned over the first working electrode but not over the second
working electrode.
[0251] FIG. 3E is a perspective view of a dual-electrode continuous
analyte sensor in one embodiment.
[0252] FIG. 3F is a schematic illustrating metabolism of glucose by
Glucose Oxidase (GOx) and one embodiment of a diffusion barrier D
that substantially prevents the diffusion of H.sub.2O.sub.2
produced on a first side of the sensor (e.g., from a first working
electrode that has active GOx) to a second side of the sensor
(e.g., to the second working electrode that lacks active GOx).
[0253] FIG. 3G is a two-dimensional schematic of a dual-electrode
sensor in one embodiment, illustrating the sensor's first and
second electroactive surfaces (of the first and second working
electrodes, respectively) beneath a sensor membrane, wherein
noise-causing species produced by a plurality of point sources can
impinge upon an electroactive surface.
[0254] FIG. 3H is a two-dimensional schematic of a dual-electrode
sensor in one embodiment, illustrating the sensor's first and
second electroactive surfaces (of the first and second working
electrodes, respectively) beneath a sensor membrane, wherein noise
from a single point source (e.g., a cell) can impinge upon both
electroactive surfaces.
[0255] FIG. 3I is a cross-sectional schematic illustrating a
dual-electrode sensor, in one embodiment, including a physical
diffusion barrier.
[0256] FIG. 3J is a graph illustrating signal response of the
electrodes of a dual-electrode sensor, in one embodiment.
[0257] FIG. 3K is a graph illustrating signal response of the
electrodes of a dual-electrode sensor, in one embodiment.
[0258] FIG. 4 is a graph illustrating in vivo function of an
analyte sensor system of the embodiment shown in FIG. 1A.
[0259] FIG. 5 is a graph illustrating in vivo function of an
analyte sensor system of the embodiment shown in FIG. 1A.
[0260] FIG. 6 is a schematic of an integrated sensor system.
[0261] FIG. 7 is a block diagram of an integrated sensor system
[0262] FIGS. 8A through 8C are schematic illustrations of a flow
control device in one exemplary embodiment, including is relative
movement/positions and the consequential effect on the flow of
fluids through the sensor/catheter inserted in a host.
[0263] FIG. 9 is a cut-away illustration of one exemplary
embodiment of a catheter implanted in a host's vessel.
[0264] FIG. 10A is a schematic illustrating one exemplary
embodiment of a flow control device and tubing assembly.
[0265] FIG. 10B is a schematic illustrating another exemplary
embodiment of a flow control device and tubing assembly.
[0266] FIG. 10C is a schematic illustrating another exemplary
embodiment of a flow control device with installed tubing assembly,
wherein the valve is in a gravity flow position.
[0267] FIG. 10D is a schematic illustrating another exemplary
embodiment of a flow control device with installed tubing assembly,
wherein the valve is in a controlled-flow position.
[0268] FIG. 10E is a graph illustrating an exemplary flow profile,
in one embodiment.
[0269] FIG. 11 is a graph that schematically illustrates a signal
produced during exposure of the sensor to a step change in analyte
concentration, in one exemplary embodiment.
[0270] FIG. 12 is a graph that schematically illustrates a
derivative of the step response shown in FIG. 9.
[0271] FIG. 13 is a graph that illustrates level vs. rate for a
plurality of time-spaced signals associated with exposure of the
sensor to biological samples of unknown or uncalibrated analyte
concentration.
[0272] FIG. 14 is a flow chart illustrating sensor sensitivity
evaluation, in one embodiment.
[0273] FIG. 15 is a flow chart illustrating sensor stability
evaluation, in one embodiment.
[0274] FIG. 16 is a flow chart illustrating system diagnostics, in
one embodiment.
[0275] FIG. 17 is a graphical representation showing exemplary
glucose sensor data and corresponding blood glucose values over
time in a pig.
[0276] FIG. 18 is a graphical representation showing exemplary
calibrated glucose sensor data (test) and corresponding blood
glucose values (YSI control) over time in a human.
[0277] FIG. 19A is a graph that illustrates an in vivo signal
(counts) detected from a dual-electrode sensor, in one embodiment,
implanted in a non-diabetic human host.
[0278] FIG. 19B is a graph that illustrates an in vivo signal
(counts) detected from a dual-electrode, in another embodiment,
implanted in a non-diabetic human host.
[0279] FIG. 20A is a graph that illustrates an in vivo signal
(counts) detected from a dual-electrode, in one embodiment,
implanted in a non-diabetic human host.
[0280] FIG. 20B is a graph that illustrates an in vivo signal
(counts) detected from a dual-electrode, in another embodiment,
implanted in a non-diabetic human host.
[0281] FIG. 21A is a graph that illustrates an in vivo glucose
values detected from a dual-electrode, in another embodiment,
implanted in a non-diabetic porcine host.
[0282] FIG. 21B is a Clark Error Grid graph of the data of FIG.
21A.
[0283] FIG. 22 is a graph of a signal waveform generated during a
successful infusion of the reference solution into the host versus
the adaptive calibration waveform template.
[0284] FIG. 23 is a graph of a signal waveform generated during an
unsuccessful infusion of the reference solution into the host
versus the adaptive calibration waveform template.
[0285] FIG. 24 is a graph of the signals generated from the
plus-enzyme working electrode and from the no-enzyme working
electrode illustrating sensor stabilization.
[0286] FIG. 25 is a graph illustrating sensor sensitivity over
time.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0287] 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 preferred
embodiments.
Definitions
[0288] In order to facilitate an understanding of the preferred
embodiments, a number of terms are defined below.
[0289] 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 is not to be limited to a special or
customized meaning), and refers without limitation to a substance
or chemical constituent in a biological sample (e.g., bodily
fluids, including, blood, serum, plasma, interstitial fluid,
cerebral spinal fluid, lymph fluid, ocular fluid, saliva, oral
fluid, urine, excretions or exudates). Analytes can include
naturally occurring substances, artificial substances, metabolites,
and/or reaction products. In some embodiments, the analyte for
measurement by the sensing regions, devices, and methods is
albumin, alkaline phosphatase, alanine transaminase, aspartate
aminotransferase, bilirubin, blood urea nitrogen, calcium,
CO.sub.2, chloride, creatinine, glucose, gamma-glutamyl
transpeptidase, hematocrit, lactate, lactate dehydrogenase,
magnesium, oxygen, pH, phosphorus, potassium, sodium, total
protein, uric acid, metabolic markers, and drugs. However, other
analytes are contemplated as well, including but not limited to
acetaminophen, dopamine, ephedrine, terbutaline, ascorbate, uric
acid, oxygen, d-amino acid oxidase, plasma amine oxidase, xanthine
oxidase, NADPH oxidase, alcohol oxidase, alcohol dehydrogenase,
pyruvate dehydrogenase, diols, Ros, NO, bilirubin, cholesterol,
triglycerides, gentisic acid, ibuprophen, L-Dopa, methyl dopa,
salicylates, tetracycline, tolazamide, tolbutamide,
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- hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S,
hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab,
beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber
hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,
sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;
dihydropteridine reductase; diptheria/tetanus antitoxin;
erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty
acids/acylglycines; free -human chorionic gonadotropin; free
erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine
(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;
galactose-1-phosphate uridyltransferase; gentamicin;
glucose-6-phosphate dehydrogenase; glutathione; glutathione
perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1, ); 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), Schistosoma mansoni, Toxoplasma gondii, Trepenoma
pallidium, Trypanosoma cruzi/rangeli, 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 can
also constitute analytes in certain embodiments. The analyte can be
naturally present in the biological fluid, for example, a metabolic
product, a hormone, an antigen, an antibody, and the like.
Alternatively, the analyte can be introduced into the body, for
example, a contrast agent for imaging, a radioisotope, a chemical
agent, a fluorocarbon-based synthetic blood, or a drug or
pharmaceutical composition, including but not limited to insulin;
ethanol; cannabis (marijuana, tetrahydrocannabinol, hashish);
inhalants (nitrous oxide, amyl nitrite, butyl nitrite,
chlorohydrocarbons, hydrocarbons); cocaine (crack cocaine);
stimulants (amphetamines, methamphetamines, Ritalin, Cylert,
Preludin, Didrex, PreState, Voranil, Sandrex, Plegine); depressants
(barbituates, methaqualone, tranquilizers such as Valium, Librium,
Miltown, Serax, Equanil, Tranxene); hallucinogens (phencyclidine,
lysergic acid, mescaline, peyote, psilocybin); narcotics (heroin,
codeine, morphine, opium, meperidine, Percocet, Percodan,
Tussionex, Fentanyl, Darvon, Talwin, Lomotil); designer drugs
(analogs of fentanyl, meperidine, amphetamines, methamphetamines,
and phencyclidine, for example, Ecstasy); anabolic steroids; and
nicotine. The metabolic products of drugs and pharmaceutical
compositions are also contemplated analytes. Analytes such as
neurochemicals and other chemicals generated within the body can
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), histamine, Advanced Glycation End
Products (AGEs) and 5-hydroxyindoleacetic acid (FHIAA).
[0290] The term "antegrade" 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 are not to be limited to a special
or customized meaning), and refers without limitation to
orientation (e.g., of a catheter) with the direction of blood
flow.
[0291] The term "baseline," "noise" and "background signal" 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 a component of an analyte sensor signal that
is not related to the analyte concentration. 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/reduction 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 baseline, or background, of the
signal.
[0292] The terms "baseline and/or sensitivity shift," "baseline
and/or sensitivity drift," "shift," and "drift" 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 are not to be
limited to a special or customized meaning), and refer without
limitation to a change in the baseline and/or sensitivity of the
sensor signal over time. While the term "shift" generally refers to
a substantially distinct change over a relatively short time
period, and the term "drift" generally refers to a substantially
gradual change over a relatively longer time period, the terms can
be used interchangeably and can also be generally referred to as
"change" in baseline and/or sensitivity.
[0293] 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, serum, plasma,
interstitial fluid, cerebral spinal fluid, lymph fluid, ocular
fluid, saliva, oral fluid, urine, sweat, excretions, exudates, and
the like.
[0294] The term "blood chemistry analysis device" 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 are not to be limited
to a special or customized meaning), and refers without limitation
to a device that measures a variety of blood components,
characteristics or analytes therein. In one embodiment, a blood
chemistry analysis device periodically withdraws an aliquot of
blood from the host, measures glucose, O.sub.2, CO.sub.2,
PCO.sub.2, PO.sub.2, potassium, sodium, pH, lactate, urea,
bilirubin, creatinine, hematocrit, various minerals, and/or various
metabolites, and the like, and returns the blood to the host's
circulatory system. A variety of devices exist for testing various
blood properties/analytes at the bedside, such as but not limited
to the blood gas and chemistry devices manufactured by Via Medical
(Austin, Tex., USA).
[0295] The term "blood pressure monitor" 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 are not to be limited to a
special or customized meaning), and refers without limitation to an
instrument for monitoring the blood pressure of a human or other
animal. For example, a blood pressure monitor can be an invasive
blood pressure monitor, which periodically monitors the host's
blood pressure via a peripheral artery, using a blood pressure
transducer, such as but not limited to a disposable blood pressure
transducer. Utah Medical Products Inc. (Midvale, Utah, USA)
produces a variety of DELTRAN.RTM. Brand disposable blood pressure
transducers that are suitable for use with various embodiments
disclosed herein.
[0296] 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 is not to be limited to a special or
customized meaning), and refers without limitation to the
relationship and/or process of determining the relationship between
the sensor data and the corresponding reference data, which can be
used to convert sensor data into values substantially equivalent to
the reference data. In some embodiments, namely, in continuous
analyte sensors, calibration can be updated or recalibrated over
time if changes in the relationship between the sensor data and
reference data occur, for example, due to changes in sensitivity,
baseline, transport, metabolism, and the like.
[0297] The term "casting" 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 process
where a fluid material is applied to a surface or surfaces and
allowed to cure or dry. The term is broad enough to encompass a
variety of coating techniques, for example, using a draw-down
machine (i.e., drawing-down), dip coating, spray coating, spin
coating, and the like.
[0298] The term "catheter" 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 are not to be limited to a special
or customized meaning), and refers without limitation to a tube
that can be inserted into a host's body (e.g., cavity, duct or
vessel). In some circumstances, catheters allow drainage or
injection of fluids or access by medical instruments or devices. In
some embodiments, a catheter is a thin, flexible tube (e.g., a
"soft" catheter). In alternative embodiments, the catheter can be a
larger, solid tube (e.g., a "hard" catheter). The term "cannula" is
interchangeable with the term "catheter" herein.
[0299] The term "coaxial" as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and it is not to be limited to a special or
customized meaning), and refers without limitation to having a
common axis, having coincident axes or mounted on concentric
shafts.
[0300] 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.
[0301] The terms "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.
[0302] The terms "continuous" and "continuously" as used herein are
broad terms, and are to be given their ordinary and customary
meanings to a person of ordinary skill in the art (and are not to
be limited to a special or customized meaning), and refer without
limitation to the condition of being marked by substantially
uninterrupted extension in space, time or sequence. In one
embodiment, an analyte concentration is measured continuously or
continually, for example at time intervals ranging from fractions
of a second up to, for example, about 1, 2, 5, 10, 15, 20, 30, 40,
50 or 60 minutes, or longer. It should be understood that
continuous glucose sensors generally continually measure glucose
concentration without required user initiation and/or interaction
for each measurement, such as described with reference to U.S. Pat.
No. 6,001,067, for example. These terms include situations wherein
data gaps can exist (e.g., when a continuous glucose sensor is
temporarily not providing data).
[0303] The term "continuous (or continual) analyte 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 is
not to be limited to a special or customized meaning), and refers
without limitation to the period in which monitoring of analyte
concentration is continuously, continually, and or intermittently
(regularly or irregularly) performed, for example, about every 5 to
10 minutes.
[0304] The term "count" 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 unit of
measurement of a digital signal. For example, a raw data stream or
raw data signal measured in counts is directly related to a voltage
(for example, converted by an A/D converter), which is directly
related to current from the working electrode. In some embodiments,
the terms can refer to data that has been integrated or averaged
over a time period (e.g., 5 minutes).
[0305] The terms "coupling" and "operatively coupling" as used
herein are broad terms, and are to be given their ordinary and
customary meanings to a person of ordinary skill in the art (and
are not to be limited to a special or customized meaning), and
refer without limitation to a joining or linking together of two or
more things, such as two parts of a device or two devices, such
that the things can function together. In one example, two
containers can be operatively coupled by tubing, such that fluid
can flow from one container to another. Coupling does not imply a
physical connection. For example, a transmitter and a receiver can
be operatively coupled by radio frequency (RF)
transmission/communication.
[0306] 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.
[0307] The term "dip coating" 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 coating,
which involves dipping an object or material into a liquid coating
substance.
[0308] The term "distal to" 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 spatial
relationship between various elements in comparison to a particular
point of reference. In general, the term indicates an element is
located relatively far from the reference point than another
element.
[0309] 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 is not to be limited to a special or
customized meaning), and refers without limitation to a region of
the membrane system that can be a layer, a uniform or non-uniform
gradient (for example, an anisotropic region of a membrane), or a
portion of a membrane.
[0310] The term "electrochemical break-in" 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 time, after in vitro and/or in vivo settling of the current
output from the sensor following the application of the potential
to the sensor.
[0311] 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 is not to be
limited to a special or customized meaning), and refers without
limitation to a surface where an electrochemical reaction takes
place. For example, a working electrode measures hydrogen peroxide
produced by the enzyme-catalyzed reaction of the analyte detected,
which reacts to create an electric current. Glucose analyte can be
detected utilizing glucose oxidase, which produces H.sub.2O.sub.2
as a byproduct. H.sub.2O.sub.2 reacts with the surface of the
working electrode, producing two protons (2H.sup.+), two electrons
(2e.sup.-) and one molecule of oxygen (O.sub.2), which produces the
electronic current being detected.
[0312] The terms "electronic connection," "electrical connection,"
"electrical contact" 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 any connection
between two electrical conductors known to those in the art. In one
embodiment, electrodes are in electrical connection with the
electronic circuitry of a device.
[0313] The terms "electronics" and "sensor electronics" 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 are
not to be limited to a special or customized meaning), and refer
without limitation to electronics operatively coupled to the sensor
and configured to measure, process, receive, and/or transmit data
associated with a sensor. In some embodiments, the electronics
include at least a potentiostat that provides a bias to the
electrodes and measures a current to provide the raw data signal.
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, and/or transmitter. In some
embodiments, the potentiostat converts the raw data (e.g., raw
counts) collected from the sensor and converts it 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 blood (e.g., mg/dl). In some embodiments,
the sensor electronics include a transmitter that transmits the
signals from the potentiostat to a receiver (e.g., a remote
analyzer, such as but not limited to a remote analyzer unit), where
additional data analysis and glucose concentration determination
can occur.
[0314] The term "ex 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 is not to be limited to a special
or customized meaning), and refers without limitation to a portion
of a device (for example, a sensor) adapted to remain and/or exist
outside of a living body of a host.
[0315] The term "fluid communication" 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 are not to be limited to a
special or customized meaning), and refers without limitation to
two or more components (e.g., things such as parts of a body or
parts of a device) functionally linked such that fluid can move
from one component to another. These terms do not imply
directionality.
[0316] 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).
[0317] 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.
[0318] 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 is not to be limited to a special or
customized meaning), and refers without limitation to animals or
plants, for example humans.
[0319] The term "hyperglycemia" 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 are not to be limited to a special
or customized meaning), and refers without limitation to a
condition in which an excessive or high amount of glucose exists in
a host. Hyperglycemia is one of the classic symptoms of diabetes
mellitus. Non-diabetic hyperglycemia is associated with obesity and
certain eating disorders, such as bulimia nervosa. Hyperglycemia is
also associated with other diseases (or medications) affecting
pancreatic function, such as pancreatic cancer. Hyperglycemia is
also associated with poor medical outcomes in a variety of clinical
settings, such as intensive or critical care settings.
[0320] The term "hypoglycemia" 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 are not to be limited to a special
or customized meaning), and refers without limitation to a
condition in which a limited or low amount of glucose exists in a
host. Hypoglycemia can produce a variety of symptoms and effects
but the principal problems arise from an inadequate supply of
glucose as fuel to the brain, resulting in impairment of function
(neuroglycopenia). Derangements of function can range from vaguely
"feeling bad" to coma, and (rarely) permanent brain damage or
death.
[0321] 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.
[0322] The term "indwell" 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 are not to be limited to a special or
customized meaning), and refers without limitation to reside within
a host's body. Some medical devices can indwell within a host's
body for various lengths of time, depending upon the purpose of the
medical device, such as but not limited to a few hours, days, or
weeks, to months, years, or even the host's entire lifetime. In one
exemplary embodiment, an arterial catheter may indwell within the
host's artery for a few hours, days, a week, or longer, such as but
not limited to the host's perioperative period (e.g., from the time
the host is admitted to the hospital to the time he is
discharged).
[0323] 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.
[0324] 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).
[0325] 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/reduction
potential that overlaps with the analyte to be measured, producing
a false positive signal. In another example of an electrochemical
sensor, interfering species are substantially non-constant
compounds (e.g., the concentration of an interfering species
fluctuates over time). Interfering species include but are not
limited to compounds with electroactive acidic, amine or sulfhydryl
groups, urea, lactic acid, phosphates, citrates, peroxides, amino
acids, amino acid precursors or break-down products, nitric oxide
(NO), NO-donors, NO-precursors, acetaminophen, ascorbic acid,
bilirubin, cholesterol, creatinine, dopamine, ephedrine, ibuprofen,
L-dopa, methyl dopa, salicylate, tetracycline, tolazamide,
tolbutamide, triglycerides, and uric acid electroactive species
produced during cell metabolism and/or wound healing, electroactive
species that arise during body pH changes and the like.
[0326] 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 is not to be limited to a special
or customized meaning), and refers without limitation to a portion
of a device (for example, a sensor) adapted for insertion into
and/or existence within a living body of a host.
[0327] The term "medical device" 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 are not to be limited to a
special or customized meaning), and refers without limitation to an
instrument, apparatus, implement, machine, contrivance, implant, in
vitro reagent, or other similar or related article, including a
component part, or accessory which is intended for use in the
diagnosis of disease or other conditions, or in the cure,
mitigation, treatment, or prevention of disease, in man or other
animals, or intended to affect the structure or any function of the
body of man or other animals. Medical devices that can be used in
conjunction with various embodiments of the analyte sensor system
include any monitoring device requiring placement in a human
vessel, duct or body cavity, a dialysis machine, a heart-lung
bypass machine, blood collection equipment, a blood pressure
monitor, an automated blood chemistry analysis device and the
like.
[0328] The terms "membrane" and "membrane system" 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 are not to be
limited to a special or customized meaning), and refer 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 one or more microns in thickness, which is permeable
to oxygen and to an analyte, e.g., glucose or another analyte. In
one example, the membrane system includes an immobilized glucose
oxidase enzyme, which enables a reaction to occur between glucose
and oxygen whereby a concentration of glucose can be measured.
[0329] The term "membrane break-in" 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
equilibration of the membrane to its surrounding environment (e.g.,
physiological environment in vivo).
[0330] The term "needle" 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 slender
hollow instrument for introducing material into or removing
material from the body.
[0331] The term "non-constant noise" or non-constant background" as
used herein are broad terms, and are to be given their ordinary and
customary meaning to a person of ordinary skill in the art (and it
is not to be limited to a special or customized meaning), and refer
without limitation to a component of the background signal that is
relatively non-constant, for example, transient and/or
intermittent. For example, certain electroactive compounds, are
relatively non-constant (e.g., intermittent interferents due to the
host's ingestion, metabolism, wound healing, and other mechanical,
chemical and/or biochemical factors), which create intermittent
(e.g., non-constant) "noise" on the sensor signal that can be
difficult to "calibrate out" using a standard calibration equations
(e.g., because the background of the signal does not remain
constant).
[0332] The term "non-enzymatic" as used herein is a broad term, and
is to be given their ordinary and customary meaning to a person of
ordinary skill in the art (and it is not to be limited to a special
or customized meaning), and refers without limitation to a lack of
enzyme activity. In some embodiments, a "non-enzymatic" membrane
portion contains no enzyme; while in other embodiments, the
"non-enzymatic" membrane portion contains inactive enzyme. In some
embodiments, an enzyme solution containing inactive enzyme or no
enzyme is applied.
[0333] The terms "operatively connected," "operatively linked,"
"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 are not to be
limited to a special or customized meaning), and refer without
limitation to one or more components linked to one or more other
components. The terms can refer to a mechanical connection, an
electrical connection, or any connection that allows transmission
of signals between the components. For example, one or more
electrodes can be used to detect the amount of analyte in a sample
and to convert that information into a signal; the signal can then
be transmitted to a circuit. In such an example, the electrode is
"operably linked" to the electronic circuitry. The terms include
wired and wireless connections.
[0334] 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 is not to be limited to a special or
customized meaning), and refers without limitation to an electronic
instrument that controls the electrical potential between the
working and reference electrodes at one or more preset values.
Typically, a potentiostat works to keep the potential constant by
noticing changes in the resistance of the system and compensating
inversely with a change in the current. As a result, a change to a
higher resistance would cause the current to decrease to keep the
voltage constant in the system. In some embodiments, a potentiostat
forces whatever current is necessary to flow between the working
and 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.
[0335] The term "pressure transducer" 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 are not to be limited to a
special or customized meaning), and refers without limitation to a
component of an intra-arterial blood pressure monitor that measures
the host's blood pressure.
[0336] 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 are
not to be limited to a special or customized meaning), and refer
without limitation to a computer system, state machine, processor,
and the like designed to perform arithmetic or logic operations
using logic circuitry that responds to and processes the basic
instructions that drive a computer.
[0337] The term "proximal to" 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 spatial
relationship between various elements in comparison to a particular
point of reference. In general, the term indicates an element is
located relatively near to the reference point than another
element.
[0338] The term "pump" 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 are not to be limited to a special or
customized meaning), and refers without limitation to a device used
to move liquids, or slurries. In general, a pump moves liquids from
lower pressure to higher pressure, and overcomes this difference in
pressure by adding energy to the system (such as a water
system).
[0339] The term "sensor break-in" 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 time
(after implantation) during which the sensor's signal is becoming
substantially representative of the analyte (e.g., glucose)
concentration (e.g., where the current output from the sensor is
stable relative to the glucose level). The signal may not be `flat`
when the sensor has broken-in, but in general, variation in the
signal level at that point is due to a change in the analyte (e.g.,
glucose) concentration. In some embodiments, sensor break-in occurs
prior to obtaining a meaningful calibration of the sensor output.
In some embodiments, sensor break-in generally includes both
electrochemical break-in and membrane break-in.
[0340] The terms "small diameter sensor," "small structured
sensor," and "micro-sensor" 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 are not to be limited to a special
or customized meaning), and refer without limitation to sensing
mechanisms that are less than about 2 mm in at least one dimension,
and more preferably less than about 1 mm in at least one dimension.
In some embodiments, the sensing mechanism (sensor) is less than
about 0.95, 0.9, 0.85, 0.8, 0.75, 0.7, 0.65, 0.6, 0.5, 0.4, 0.3,
0.2, or 0.1 mm. In some embodiments, the sensing mechanism is a
needle-type sensor, wherein the diameter is less than about 1 mm
(see, for example, U.S. Pat. No. 6,613,379 and U.S. Patent
Publication No. US-2006-0020187-A1, each of which is incorporated
herein by reference in its entirety). In some alternative
embodiments, the sensing mechanism includes electrodes deposited on
a planar substrate, wherein the thickness of the implantable
portion is less than about 1 mm, see, for example U.S. Pat. Nos.
6,175,752 and 5,779,665, both of which are incorporated herein by
reference in their entirety.
[0341] The terms "raw data," "raw data stream", "raw data signal",
"data signal", 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 are not to be limited to a
special or customized meaning), and refer without limitation to an
analog or digital signal from the analyte sensor directly related
to the measured analyte. For 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 can include a plurality of time
spaced data points from a substantially continuous analyte sensor,
each of which includes 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, the terms can refer
to data that has been integrated or averaged over a time period
(e.g., 5 minutes).
[0342] The term "regulator" or "flow control device," 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 are
not to be limited to a special or customized meaning), and refer
without limitation to a device that regulates the flow of a fluid
or gas, for example, a valve or a pump.
[0343] The term "retrograde" 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 are not to be limited to a special
or customized meaning), and refers without limitation to
orientation (e.g., of a catheter) against the direction of blood
flow.
[0344] 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 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.
[0345] The terms "sensitivity" and "slope" 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 are not to be limited to
a special or customized meaning), and refer without limitation to
an amount of electrical current produced by a predetermined amount
(unit) of the measured analyte. For example, in one preferred
embodiment, a glucose sensor has a sensitivity (or slope) of from
about 1 to about 25 picoAmps of current for every 1 mg/dL of
glucose.
[0346] The terms "sensor" and "sensor system" 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 are not to be
limited to a special or customized meaning), and refer without
limitation to a device, component, or region of a device by which
an analyte can be quantified.
[0347] The term "sheath" 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 are not to be limited to a special or
customized meaning), and refers without limitation to a covering or
supporting structure that fits closely around something, for
example, in the way that a sheath covers a blade. In one exemplary
embodiment, a sheath is a slender, flexible, polymer tube that
covers and supports a wire-type sensor prior to and during
insertion of the sensor into a catheter.
[0348] The term "single point glucose monitor" 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 device that can be used to measure a glucose concentration
within a host at a single point in time, for example, some
embodiments utilize a small volume in vitro glucose monitor that
includes an enzyme membrane such as described with reference to
U.S. Pat. Nos. 4,994,167 and 4,757,022. It should be understood
that single point glucose monitors can measure multiple samples
(for example, blood, or interstitial fluid); however only one
sample is measured at a time and typically requires some user
initiation and/or interaction.
[0349] The term "slot" 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 are not to be limited to a special or
customized meaning), and refers without limitation to a relatively
narrow opening.
[0350] The terms "solvent" and "solvent system" 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 are not to be
limited to a special or customized meaning), and refer without
limitation to substances (e.g., liquids) capable of dissolving or
dispersing one or more other substances. Solvents and solvent
systems can include compounds and/or solutions that include
components in addition to the solvent itself.
[0351] The term "specific gravity" 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 ratio
of density of a material (e.g., a liquid or a solid) to the density
of distilled water.
[0352] The term "spin coating" 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 coating
process in which a thin film is created by dropping a raw material
solution onto a substrate while it is rotating.
[0353] The term "spray coating" 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 coating,
which involves spraying a liquid coating substance onto an object
or material.
[0354] The terms "substantial" and "substantially" 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 are not to be
limited to a special or customized meaning), and refer without
limitation to a sufficient amount that provides a desired function.
For example, 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.
[0355] 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.
[0356] The term "valve" 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 are not to be limited to a special or
customized meaning), and refers without limitation to a device that
regulates the flow of substances (either gases, fluidized solids,
slurries, or liquids), for example, by opening, closing, or
partially obstructing a passageway through which the substance
flows. In general, a valve allows no flow, free flow and/or gravity
flow and/or metered flow through movement of the valve between one
or more discreet positions.
[0357] The term "vascular access device" 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 are not to be limited to a
special or customized meaning), and refers without limitation to
any device that is in communication with the vascular system of a
host. Vascular access devices include but are not limited to
catheters, shunts, blood withdrawal devices, connectors, valves,
tubing and the like.
Overview
[0358] Intensive care medicine or critical care medicine is
concerned with providing greater than ordinary medical care and/or
observation to people in a critical or unstable condition. In
recent years, an increasingly urgent need has arisen, for more
intensive care medicine. People requiring intensive care include
those recovering after major surgery, with severe head trauma,
life-threatening acute illness, respiratory insufficiency, coma,
hemodynamic insufficiency, severe fluid imbalance or with the
failure of one or more of the major organ systems (life-critical
systems or others). More than five million people are admitted
annually to intensive care units (ICUs) and critical care units
(CCUs) in the United States.
[0359] Intensive care is generally the most expensive, high
technology and resource intensive area of medical care. In the
United States estimates of the year 2000 expenditure for critical
care medicine ranged from $15-55 billion accounting for about 0.5%
of GDP and about 13% of national health care expenditure. As the
U.S. population ages, these costs will increase substantially.
Accordingly, there is an urgent need to reduce costs while at the
same time reducing ICU/CCU mortality rates by improving care.
[0360] Intensive medical care requires frequent testing and/or
monitoring of a variety of analytes, such as but not limited to
albumin, alkaline phosphatase, alanine transaminase, aspartate
aminotransferase, bilirubin, blood urea nitrogen, calcium,
CO.sub.2, chloride, creatinine, glucose, gamma-glutamyl
transpeptidase, hematocrit, lactate, lactate dehydrogenase,
magnesium, oxygen, pH, phosphorus, potassium, sodium, total
protein, uric acid, a metabolic marker and a drug. Some embodiments
disclosed herein are suitable for use in an intensive care or
critical care unit of a medical care facility for substantially
continuously measuring the concentration of one or more analytes in
the host.
[0361] For example, diabetes is one medical condition requiring
frequent testing of the host's analyte levels (e.g., blood glucose
levels), in hospital settings. Hosts having diabetes, for example,
are at risk of developing hyperglycemia, a medical condition in
which an excessive amount of glucose circulates in a host.
Perioperative hyperglycemia is associated with increased rates and
severity of myocardial infarction (MI) and stroke, while tight
glucose control with intravenous (IV) insulin therapy is linked to
a 30% reduction in mortality one year after admission for acute MI.
Furthermore, strict in-hospital glucose control is associated with
40% reductions of morbidity, mortality, sepsis, dialysis, blood
transfusions, as well as reduced length of stay, reduced costs and
the like. On the other hand, diabetic hosts are also susceptible to
hypoglycemia (e.g., excessively low circulating blood glucose),
which can cause shock and death (immediate problems), which the
clinical staff rigorously avoids, often by maintaining the host at
elevated blood glucose concentrations (which can degrade the
clinical outcome in the long run) and causes the problems of
hyperglycemia discussed above. Unfortunately, using generally
available technology, tight glucose control requires frequent
monitoring of the host by the clinical staff, IV insulin or
injections, and on-time feeding. Frequent monitoring typically
requires a nurse or other staff member to measure the host's
glucose concentration using a lancet (to obtain a blood sample) and
a hand held glucose monitor. The nurse can perform this task many
times a day (e.g., every hour or more frequently). This task
becomes an undue burden that takes the nurse away from his/her
other duties, or requires extra staff. In spite of clinically
demonstrated improvements associated with tight glucose control,
institutions are slow to adopt the therapy due to the increased
workload on the staff as well as a pervasive fear of hypoglycemia,
which is potentially life ending.
[0362] Therefore, there is an urgent need for devices and methods
that offer continuous, robust analyte monitoring, to improve
patient care and lower medical costs. Some embodiments disclose
systems and methods to reduce and/or minimize the interaction
required to regularly (e.g., continuously) measure the host's
glucose concentration. Additional and/or alternative analytes can
also be continuously monitored using the devices and methods of the
preferred embodiments. The preferred embodiments describe systems
and methods for providing continuous analyte monitoring while
providing alarms or alerts that aid in avoiding adverse events.
[0363] The in vivo continuous analyte monitoring system of the
preferred embodiments can be used in clinical settings, such as in
the hospital, the doctor's office, long-term nursing facilities, or
even in the home. The present device can be used in any setting in
which frequent or continuous analyte monitoring is desirable. For
example, in the ICU, hosts are often recovering from serious
illness, disease, or surgery, and control of host glucose levels is
important for host recovery. For example, use of a continuous
glucose sensor as described in the some embodiments allows tight
control of host glucose concentration and improved host care, while
reducing hypoglycemic episodes and reducing the ICU staff work
load. For example, the system can be used for the entire hospital
stay or for only a part of the hospital stay.
[0364] In another example, the continuous glucose monitor of the
preferred embodiments can be used in medical settings wherein the
host is unable to communicate with the medical staff, such as an ER
setting. For example, in the ER, a host may be unconscious and
therefore unable to communicate with the staff. In another example,
a very young, non-verbal host may also be unable to communicate
with the staff regarding his or her condition. In still another
example, a host undergoing surgery is unable to communicate with
the anesthesiologist, due to certain drugs being delivered. Routine
use of a continuous analyte monitors (e.g., glucose, calcium,
sodium, potassium, CO.sub.2, chloride, blood urea nitrogen,
creatinine, pH, oxygen, albumin, total protein, alkaline
phosphatase, alanine amino transferase, aspartate amino
transferase, bilirubin, phosphate, electrolytes, hematocrit and/or
drugs) can enable medical staff to monitor and respond to analyte
concentration changes indicative of the host's condition without
host input.
[0365] In yet another example, a continuous analyte monitor can be
used in the general hospital population to monitor host analyte
concentrations, for various lengths of time, such as during the
entire hospital stay or for a portion of the hospital stay (e.g.,
only during surgery). For example, a diabetic host's glucose
concentration can be monitored during his or her entire stay. In
another example, a cardiac host's glucose can be monitored during
surgery and while in the ICU, but not after being moved to the
general host population. In another example, a jaundiced newborn
infant can have his or her bilirubin concentration continuously
monitored by an in-dwelling continuous analyte monitor until the
condition has receded.
[0366] In addition to use in the circulatory system, the analyte
sensor of the preferred embodiments can be used in other body
locations. In some embodiments, the sensor is used subcutaneously.
In another embodiment, the sensor can be used intracranially. In
another embodiment, the sensor can be used within the spinal
compartment, such as but not limited to the epidural space. In some
embodiments, the sensor of the preferred embodiments can be used
with or without a catheter.
[0367] Applications/Uses
[0368] One aspect of the preferred embodiments provides a system
for in vivo continuous analyte monitoring (e.g., albumin, alkaline
phosphatase, alanine transaminase, aspartate aminotransferase,
bilirubin, blood urea nitrogen, calcium, CO.sub.2, chloride,
creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit,
lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus,
potassium, sodium, total protein, uric acid, a metabolic marker, a
drug, various minerals, various metabolites, and the like) that can
be operatively coupled to a catheter to measure analyte
concentration within the host's blood stream. In some embodiments,
the system includes an analyte sensor that extends a short distance
into the blood stream (e.g., out of the catheter) without
substantially occluding the catheter or the host's blood stream.
The catheter can be fluidly coupled to additional IV and diagnostic
devices, such as a saline bag, an automated blood pressure monitor,
or a blood chemistry monitor device. In some embodiments, blood
samples can be removed from the host via the sensor system, as
described elsewhere herein. In one embodiment, the sensor is a
glucose sensor, and the medical staff monitors the host's glucose
level. In other embodiments, described elsewhere herein, the
analyte sensor is disposed within or on the catheter itself, such
as the in vivo portion of the catheter. In still other embodiments,
the analyte sensor is disposed entirely within and/or on the fluid
coupler, which is in turn fluidly coupled to a catheter or other
vascular access device, as described elsewhere herein.
[0369] FIGS. 1A to 1J illustrate two embodiments of an exemplary
analyte sensor system 10 for measuring an analyte, as described
elsewhere herein, that includes a catheter 12 configured to be
inserted or pre-inserted into a host's blood stream. In clinical
settings, catheters are often inserted into hosts to allow direct
access to the circulatory system without frequent needle insertion
(e.g., venipuncture). Suitable catheters can be sized as is known
and appreciated by one skilled in the art, such as but not limited
to from about 1 French (0.33 mm) or less to about 30 French (10 mm)
or more; and can be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, or 20 French (3 French is
equivalent to about 1 mm) and/or from about 33 gauge or less to
about 16 gauge or more, for example, 33, 32, 31, 30, 29, 28, 27,
26, 25, 24, 23, 22, 21, 20, 19, 18, 17, or 16 gauge. Additionally,
the catheter can be shorter or longer, for example 0.75, 1.0, 1.25,
1.5, 1.75, 2.0 inches in length or longer. In some embodiments, the
catheter is a venous catheter. In other embodiments, the catheter
is configured for insertion into a peripheral or a central artery.
In some embodiments, the catheter is configured to extend from a
peripheral artery to a central portion of the host's circulatory
system, such as but not limited to the heart. In still other
embodiments, the catheter is configured for insertion into neonatal
or other pediatric hosts (e.g., 22-24 gauge or smaller). The
catheter can be manufactured of any medical grade material known in
the art, such as but not limited to polymers and glass as described
herein. A catheter can include a single lumen or multiple lumens. A
catheter can include one or more perforations, to allow the passage
of host fluid through the lumen of the catheter.
[0370] The terms "inserted" or "pre-inserted" 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 are not to be
limited to a special or customized meaning), and refer without
limitation to insertion of one thing into another thing. For
example, a catheter can be inserted into a host's blood stream. In
some embodiments, a catheter is "pre-inserted," meaning inserted
before another action is taken (e.g., insertion of a catheter into
a host's blood stream prior to insertion of a sensor into the
catheter). In some exemplary embodiments, a sensor is coupled to a
pre-inserted catheter, namely, one that has been previously
inserted (or pre-inserted) into the host's circulatory system.
Alternatively, the sensor and the catheter can be configured to be
inserted together and/or the sensor can be integrally formed with
the catheter.
[0371] Referring now to FIGS. 1A to 1J, in some embodiments, the
catheter 12 is a thin, flexible tube having a lumen 12a, such as is
known in the art. In some embodiments, the catheter can be rigid;
in other embodiments, the catheter can be custom manufactured to
desired specifications (e.g., rigidity, dimensions, etc). The
catheter can be a single-lumen catheter or a multi-lumen catheter.
In some embodiments, the catheter is a peripheral catheter
configured and arranged for insertion into a peripheral vessel
(e.g., vein and/or artery) in a host's arm and/or leg. In some
embodiments, the catheter is a central catheter, configured and
arranged for insertion into a host's central vessel (e.g., internal
jugular vein, subclavian vein, femoral vein and/or pulmonary
artery). At the catheter's proximal end is a small orifice 12b for
fluid connection of the catheter to the blood stream. At the
catheter's distal end is a connector 18, such as a Leur connector
or other fluid connector known in the art.
[0372] The illustrations of FIGS. 1A to 1J show two exemplary
embodiments of the connector 18 including a flange 18a and a duct
18b. In the exemplary embodiment, the flange 18a is configured to
enable connection of the catheter to other medical equipment (e.g.,
saline bag, pressure transducer, blood chemistry device, and the
like) or capping (e.g., with a bung and the like). Although one
exemplary connector is shown, one skilled in the art appreciates a
variety of standard or custom made connectors suitable for use with
the preferred embodiments. The duct 18b is in fluid communication
with the catheter lumen and terminates in a connector orifice
18c.
[0373] In some embodiments, the catheter is inserted into the
host's blood stream, such as into a vein or artery by any useful
method known in the art. Generally, prior to and during insertion,
the catheter is supported by a hollow needle or trochar (not
shown). For example, the supported catheter can be inserted into a
peripheral vein or artery, such as in the host's arm, leg, hand, or
foot. Typically, the supporting needle is removed (e.g., pulled out
of the connector) and the catheter is connected (e.g., via the
connector 18) to IV tubing and a saline drip, for example. However,
in one embodiment, the catheter is configured to operatively couple
to medical equipment, such as but not limited to a sensor system of
the preferred embodiments. Additionally and/or alternatively, the
catheter can be configured to operatively couple to another medical
device, such as a pressure transducer, for measurement of the
host's blood pressure.
[0374] In some embodiments, the catheter and the analyte sensor are
configured to indwell within the host's blood stream in vivo. An
indwelling medical device, such as a catheter or implant, is
disposed within a portion of the body for a period of time, from a
few minutes or hours to a few days, months, or even years. An
indwelling catheter is typically inserted within a host's vein or
artery for a period of time, often 2 or more days, a month, or even
a few months. In some embodiments, the catheter can indwell in a
host's artery or vein for the length of a perioperative period
(e.g., the entire hospital stay) or for shorter or longer periods.
In some embodiments, the use of an indwelling catheter permits
continuous access of an analyte sensor to a blood stream while
simultaneously allowing continuous access to the host's blood
stream for other purposes, for example, the administration of
therapeutics (e.g., fluids, drugs, etc.), measurement of
physiologic properties (e.g., blood pressure), fluid removal, and
the like.
[0375] Referring again to FIGS. 1A to 1J, the system 10 also
includes an analyte sensor 14 configured to extend through the
catheter lumen 12a (see FIG. 1E), out of the catheter orifice 12b
and into the host's blood stream by about 0.010 inches to about 1
inch, or shorter or longer lengths. In some embodiments, however,
the sensor may not extend out of the catheter, for example, can
reside just inside the catheter tip. The sensor can extend through
the catheter in any functional manner. In some embodiments, the
sensor is configured to be held (e.g., located, disposed) on an
inner surface (e.g., the lumenal surface) or outer surface of the
catheter. In some embodiments, the sensor is deposited (e.g.,
formed) on a surface of the catheter. In some embodiments, a sensor
is attached to a surface of the catheter, such as by an adhesive
and/or welding. In some other embodiments, the sensor is configured
to "free float" within the lumen of the catheter. In some
embodiments, the sensor resides within the fluid coupler.
[0376] In some embodiments, the sensor 14 is configured to measure
the concentration of an analyte (e.g., albumin, alkaline
phosphatase, alanine transaminase, aspartate aminotransferase,
bilirubin, blood urea nitrogen, calcium, CO.sub.2, chloride,
creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit,
lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus,
potassium, sodium, total protein, uric acid, a metabolic marker,
various drugs, various minerals, various metabolites, and the like)
within the host's blood stream. In some preferred embodiments, the
sensor includes at least one electrode (see, e.g., FIG. 3B), for
example a working electrode; however any combination of working
electrode(s), reference electrode(s), and/or counter electrode(s)
can be implemented as is appreciated by one skilled in the art. For
example, in some preferred embodiments, the sensor includes at
least two working electrodes, as is described with reference to
FIGS. 3D through 3I. In still other embodiments, two or more
analyte sensors are in fluid communication with the vascular access
device (e.g., disposed within the vascular access device), such
that two or more analytes can be monitored simultaneously, and/or
sequentially, continuously and/or intermittently, and the like.
Preferably, the sensor 14 includes at least one exposed
electroactive area (e.g., working electrode), a membrane system
(e.g., including an enzyme), a reference electrode (proximal to or
remote from the working electrode), and an insulator material.
Various systems and methods for design and manufacture of
continuous analyte sensors are described in more detail elsewhere
herein. In some embodiments, the sensor is a needle-type continuous
analyte sensor, configured as disclosed in U.S. Patent Publication
No. US-2006-0020192-A1 and U.S. Patent Publication No.
US-2006-0036143-A1, both of which are incorporated herein by
reference in their entirety. In some embodiments, the sensor is
disposed on a planar substrate, configured as disclosed in U.S.
Pat. Nos. 6,175,752, 6,512,939 and 7,402,153, each of which are
incorporated herein by reference in their entirety. In some
embodiments, the sensor is configured to measure glucose
concentration. Exemplary sensor configurations are discussed in
more detail, elsewhere herein.
[0377] Referring to an embodiment illustrated in FIGS. 1A to 1E,
the sensor has a proximal end 14a and a distal end 14b. At its
distal end 14b, the sensor 14 is associated with (e.g., connected
to, held by, extends through, and the like) a fluid coupler 20
having first and second sides (20a and 20b, respectively). The
fluid coupler is configured to mate (via its first side 20a) to the
catheter connector 18. In one embodiment, a skirt 20c is located at
the fluid coupler's first side and includes an interior surface 20d
with threads 20e (see FIGS. 1D and 1E). In this embodiment, the
fluid coupler is configured to mate with the connector flange 18a,
which is screwed into the fluid coupler via the screw threads.
However, in other embodiments, the fluid coupler is configured to
mate with the connector using any known mating configuration, for
example, a snap-fit, a press-fit, an interference-fit, and the
like, and can include a locking mechanism to prevent separation of
the connector and fluid coupler. The fluid coupler 20 includes a
lumen 20f extending from a first orifice 20h on its first side 20a
to a second orifice 20i located on the fluid coupler's second side
20b (FIGS. 1C1 to 1E). When the catheter connector is mated with
the fluid coupler, the catheter's lumen 12a is in fluid
communication with the fluid coupler's lumen 20f via orifices 18c
and 20h.
[0378] FIGS. 1A to 1D show one embodiment of a fluid coupler 20,
namely, a Y-coupler; however, any known coupler configuration can
be used, including but not limited to a straight coupler, a
T-coupler, a cross-coupler, a custom configured coupler, and the
like. In some embodiments, the fluid coupler includes at least one
valve (e.g., a septum, a 3-way valve, a stop-cock valve), which can
be used for a variety of purposes (e.g., injection of drugs). As
another example, FIGS. 1F-1J illustrate a fluid coupler configured
for connection of the sensor to sensor electronics via a female
socket 20n configured to releasably mate with a male plug on an
electronic cable. The fluid coupler can be made of any convenient
material, such as but not limited to plastic, glass, metal or
combinations thereof and can be configured to withstand known
sterilization techniques.
[0379] In the exemplary embodiment, the second side 20b of the
fluid coupler 20 is configured to be operably connected to IV
equipment, another medical device or to be capped, and can use any
known mating configuration, for example, a snap-fit, a press-fit,
an interference-fit, and the like. In one exemplary embodiment, the
second side 20b is configured to mate with a saline drip, for
delivery of saline to the host. For example, the saline flows from
an elevated bag of sterile saline via tubing, through the fluid
coupler, through the catheter and into the host's blood system
(e.g., vein or artery). In another embodiment, a syringe can be
mated to the fluid coupler, for example, to withdraw blood from the
host, via the catheter. Additional connection devices (e.g., a
three-way valve) can be operably connected to the fluid coupler, to
support additional functionality and connection of various devices,
such as but not limited to a blood pressure transducer.
[0380] Referring to the exemplary embodiment of FIGS. 1A and 1E, at
least a portion of the sensor 14 passes through the fluid coupler
20 (e.g., the fluid coupler lumen 20f) and is operatively connected
to sensor electronics (not shown) via a hardwire 24. In alternative
embodiments however, the sensor electronics can be disposed in part
or in whole with the fluid coupler (e.g., integrally with or
proximal to) or can be disposed in part or in whole remotely from
the fluid coupler (e.g., on a stand or at the bed side).
Connections between the sensor and sensor electronics (in part or
in whole) can be accomplished using known wired or wireless
technology. In one exemplary embodiment, the sensor is hardwired to
the electronics located substantially wholly remote from the fluid
coupler (e.g., disposed on a stand or near the bedside); one
advantage of remote electronics includes enabling a smaller sized
fluid coupler design. In another exemplary embodiment, a portion of
the sensor electronics, such as a potentiostat, is disposed on the
fluid coupler and the remaining electronics (e.g., electronics for
receiving, data processing, printing, connection to a nurses'
station, etc.) are disposed remotely from the fluid coupler (e.g.,
on a stand or near the bedside). One advantage of this design can
include more reliable electrical connection with the sensor in some
circumstances. In this embodiment, the potentiostat can be
hardwired directly to the remaining electronics or a transmitter
can be disposed on or proximal to the fluid coupler, for remotely
connecting the potentiostat to the remaining electronics (e.g., by
radio frequency (RF)). In another exemplary embodiment, all of the
sensor electronics can be disposed on the fluid coupler. In still
another embodiment, the sensor electronics disposed on the fluid
coupler include a potentiostat.
[0381] Referring again to FIGS. 1A to 1E, a protective sheath 26 is
configured to cover at least a portion of the sensor 14 during
insertion, and includes hub 28 and slot 30. In general, the
protective sheath protects and supports the sensor prior to and
during insertion into the catheter 12 via the connector 18. The
protective sheath can be made of biocompatible polymers known in
the art, such as but not limited to polyethylene (PE), polyurethane
(PE), polyvinyl chloride (PVC), polycarbonate (PC), nylon,
polyamides, polyimide, polytetrafluoroethylene (PTFE), Teflon,
nylon and the like. The protective sheath includes a hub 28, for
grasping the sheath (e.g., while maintaining sterilization of the
sheath). In this embodiment, the hub additionally provides for
mating with the second side 20b of the fluid coupler 20, prior to
and during sensor insertion into the catheter. In this exemplary
embodiment, the slot of the protective sheath is configured to
facilitate release of the sensor therefrom. In this embodiment,
after the sensor has been inserted into the catheter, the hub is
grasped and pulled from the second side of the fluid coupler. This
action peels the protective sheath from the sensor (e.g., the
sensor slides through the slot as the sheath is removed), leaving
the sensor within the catheter. The second side of the fluid
coupler can be connected to other medical devices (e.g., a blood
pressure monitor) or an IV drip (e.g., a saline drip), or capped.
In alternative embodiments, the sheath can fold (e.g., fold back or
concertinas) or retract (e.g., telescope) during insertion, to
expose the sensor. In other embodiments, the sheath can be
configured to tear away from the sensor before, during, or after
insertion of the sensor. In still other embodiments, the sheath can
include an outlet hole 30a, to allow protrusion of the sensor from
the back end of the sheath (e.g., near the hub 28). One skilled in
the art will recognize that additional configurations can be used,
to separate the sensor 14 from the sheath 26.
[0382] In some embodiments, the sensor includes at least two
working electrodes 14, which can be twisted and/or bundled, such as
in a helical and/or coaxial configuration. In some embodiments, the
two working electrodes are twisted into a "twisted pair," which can
be configured to be inserted into and to extend within a vascular
access device, such as a catheter 12 or cannula implanted in a
host's vein or artery, as is described in more detail in the
section entitled "Integrated Sensor System." In some embodiments,
the twisted pair is configured to reside within the lumen 12a of
the catheter 12; while in other embodiments, the twisted pair is
configured to protrude from the catheter's proximal orifice 12b. In
still other embodiments, the twisted pair is configured to
intermittently protrude from the catheter's proximal orifice
12b.
[0383] In some embodiments, the sheath 26 can be optional,
depending upon the sensor design. For example, the sensor can be
inserted into a catheter or other vascular access device with or
without the use of a protective sheath). In some embodiments, the
sensor can be disposed on the outer surface of a catheter (as
described elsewhere herein) or on the inner surface of a catheter;
and no sheath is provided. In other embodiments, a multi-lumen
catheter can be provided with a sensor already disposed within one
of the lumens; wherein the catheter is inserted into the host's
vein or artery with the sensor already disposed in one of the
lumens. In one exemplary embodiment, the system includes a catheter
having multiple lumens, and is configured and arranged to infuse a
fluid in a first lumen of the catheter and to draw back a
biological sample into a second lumen of the catheter. In a further
embodiment, an analyte sensor is located in the second lumen of the
catheter. In some embodiments, the system is configured to infuse a
fluid into the second lumen, such as to reinfuse a drawn back
sample into the host and/or to wash the sensor. In some
embodiments, a flow control device is configured and arranged for
infusion of at least two solutions, such as via a multi-lumen
catheter, and includes at least two valves, such as described with
reference to FIGS. 8A through 10D.
[0384] In some alternative embodiments, an analyte sensor is
integrally formed on a catheter. In various embodiments, the
catheter can be placed into a host's vein or artery in the usual
way a catheter is inserted, as is known by one skilled in the art,
and the host's analyte concentration measured substantially
continuously. In some embodiments, the sensor system can be coupled
to one or more additional devices, such as a saline bag, an
automated blood pressure monitor, a blood chemistry monitor device,
and the like. In one exemplary embodiment, the integrally formed
analyte sensor is a glucose sensor.
[0385] FIGS. 1F through 1J illustrate another embodiment of the
sensor system, wherein the fluid coupler 20 includes a housing 20j
configured and arranged for electrical connection of the analyte
sensor 14 to at least some system electronics, such as an
electronic cable (not shown). The housing 20j includes a housing
cover 20k and an electrical connector 20n. While a female socket
20n (e.g., configured to releasably mate with a male plug) is
shown, any electrical connection known in the art can be used, as
is appreciate by one skilled in the art.
[0386] FIGS. 1G-1H are exploded and cut-away views, respectively,
of the embodiment shown in FIG. 1F. The encircled portion of FIG.
1H is shown in FIG. 1J and illustrates the configuration of the
distal portion of the analyte sensor 14 within the housing 20j, in
this embodiment. The analyte sensor can be configured and arranged
to detect one or more analytes, as described elsewhere herein. The
proximal portion (ex vivo portion) of the analyte sensor 14 is
configured and arranged for electrical connection with the sensor
electronics via one or more elastomeric contacts and/or connectors
20s and a printed circuit board (PCB) 20t disposed within the
housing. In this embodiment, the connection is a solderless
connection. However, in some embodiments, electrical connection of
the electrodes to the electronics can be made by other means, for
example, wires, contact pads, pogo pins, domed metallic contacts,
cantilevered fingers, metallic springs, soldering and/or conductive
adhesive. In the embodiment shown in FIGS. 1G-1J, an elastomeric
contact and/or connector 20s, which can be manufactured of an
conductive elastomeric material such as a carbon black elastomer,
makes an electrical connection between each of the sensor's
electrodes (e.g., working (plus or minus enzyme), counter and/or
reference electrodes) and the PCB. For example, as shown in FIG.
1J, the electrodes make contact with the elastomeric contacts, and
the elastomeric contacts make contact with the PCB. The PCB is
configured and arranged to make an electrical connection with at
least some of the system electronics, such as but not limited to by
socket 20n. Conductive elastomers are advantageously employed
because their resilient properties create a natural compression
against mutually engaging contacts, forming a secure press fit
therewith. In some embodiments, conductive elastomers can be molded
in such a way that pressing the elastomer against an adjacent
contact performs a wiping action on the surface of the contact,
thereby creating a cleaning action during initial connection.
Additionally, in some embodiments, the sensor 14 extends through
the contacts 20s wherein the sensor is electrically and
mechanically secured by the relaxation of elastomer around the
sensor.
[0387] In an alternative embodiment, a conductive, stiff plastic
forms the contacts, which are shaped to comply upon application of
pressure (for example, a leaf-spring shape). Contacts of such a
configuration can be used instead of a metallic spring, for
example, and advantageously avoid the need for crimping or
soldering through compliant materials; additionally, a wiping
action can be incorporated into the design to remove contaminants
from the surfaces during connection. Non-metallic contacts can be
advantageous because of their seamless manufacturability,
robustness to thermal compression, non-corrosive surfaces, and
native resistance to electrostatic discharge (ESD) damage due to
their higher-than-metal resistance.
[0388] While in this embodiment (e.g., shown in FIGS. 1H and 1J),
the proximal portion (e.g., part of the ex vivo portion, also
referred to herein as the first portion) of each electrode
physically contacts the bottom of (e.g., beneath) an elastomeric
connector, the electrodes can make an electrical connection with
elastomeric contacts by a variety of other ways. For example, in
some embodiments, one or more of the electrodes can contact the top
and/or side of the elastomeric contacts (e.g., above and/or
beside). In still other embodiments, an electrode can intersect an
elastomeric contact (e.g., pass through at least a portion of the
elastomeric contact). In yet another embodiment, the proximal
portion of an electrode can be wrapped around an elastomeric
contact. Additional configurations are considered in the preferred
embodiments. For example, the different configurations can be
combined, such as for example, with one electrode touching the
bottom of a first elastomeric contact, a second electrode touching
the top of a second elastomeric contact, and a third electrode
passing through yet another elastomer contact.
[0389] In some embodiments, the interior of the housing is
configured to guide placement of the electrodes for contact with
the elastomeric contacts, which can simplify manufacturing and
ensure formation of a good electrical contact between each
electrode and its corresponding elastomeric contact. For example,
in the embodiment shown in FIGS. 1H and 1J, pathways (e.g.,
recessed) are provided, to guide the placement of the electrode
wires within the housing, and wells or cups are provided to receive
the elastomeric contacts. For example, in FIG. 1G, the proximal
portion of each of the sensor's electrodes are received into one of
the three pathways provided, an elastomeric contact 20s is placed
in each of the three wells, and then the PCB 20t is placed on top
of the elastomeric contacts. Then, the housing cover 20k, which, in
some embodiments, includes a connector 20n, is applied to close the
housing.
[0390] FIG. 1K illustrates another embodiment of the analyte sensor
14 is incorporated into a fluid coupler 20. In this embodiment, the
sensor is configured such that it extends at least a portion of the
length of the lumen 20f of the fluid coupler, but does not extend
out of the fluid coupler itself (e.g., past the fluid coupler's
first orifice 20h). When the fluid coupler of this embodiment is
fluidly coupled to an implanted catheter, the first side 20a of the
fluid coupler releasably mates with the catheter hub 18, such that
a portion of the fluid coupler's first orifice 20h is located
within a portion of the catheter hub's duct or lumen (e.g., 18b,
see FIGS. 1D-1E). Accordingly, in this embodiment, the sensor tip
14a can be located within the catheter hub's duct or lumen.
Advantageously, this embodiment simplifies device installation as
no insertion of the sensor into a catheter is required.
Additionally, sensor performance is maintained because the sensor
is protected by the fluid coupler's hard structure during
connection of the fluid coupler to the catheter (e.g., the sensor
cannot be accidentally touched, bent or flexed during
installation).
[0391] As described elsewhere herein, function of an enzymatic
analyte sensor is dependent upon the kinetics of the enzyme
comprised in the sensor. For example, the function of a glucose
sensor is dependent upon the kinetics of the glucose oxidase
contained in the sensor's membrane. As is understood by one skilled
in the art, enzyme kinetics are influenced by the availability of
the reactants. When all required reactants are freely available,
the enzyme will react at its maximum rate, given the prevailing
temperature and pH conditions. If, on the other hand, the
concentration of one of the reactants is low (e.g., limiting), the
enzyme reaction will proceed at a slower rate, which is associated
with the concentration of the limited reactant. Accordingly, to
measure the concentration of a particular reactant (e.g., the
analyte), that reactant should be present in limiting amounts. In
other words, the other reactants (e.g., a co-reactant) should be
present in excess (e.g., non-limiting amounts). For example,
glucose and oxygen are the reactants of some GOX-containing glucose
sensors. Since the analyte is glucose, oxygen (e.g., the
co-reactant) should be present in excess (e.g., non-limiting), so
that the reaction rate is dependent upon the glucose concentration.
In some circumstances, however, the co-reactant is limiting. For
example, if ischemia occurs around and/or near the sensor, the
amount of available oxygen can be reduced and thus become the
limiting reactant. In another example, the analyte can exist in
excess (e.g., in the body) relative to the concentration of a
reactant, such as oxygen. In some embodiments, the sensor is
configured to compensate for a limiting reactant, such as but not
limited to oxygen. For example, the membrane can be configured and
arranged to restrict the amount of excess reactant that diffuses
therethrough (e.g., see the section entitled "Resistance Domain.")
In other embodiments, the sensor can be configured to increase the
level of limiting reactant (e.g., co-reactant). For example, in
some embodiments, the membrane can include a domain configured to
increase the concentration of oxygen. In other embodiments, the
vascular access device, such as the ex vivo portion of a catheter
or a fluid coupler can be configured to increase the amount of
oxygen (e.g., co-reactant) available to the enzyme. For example,
the fluid coupler 20 of FIG. 1K includes an enrichment body 20p
configured and arranged to increase the oxygen concentration at the
sensor 14. An enrichment body 20p can be provided in many forms.
For example, in the embodiment shown in FIG. 1K, the enrichment
body includes an "oxygen port" including a membrane, plug or filter
located in a side of the fluid coupler. In this embodiment, the
oxygen port intersects the fluid coupler wall, such that oxygen can
diffuse from the exterior of the fluid coupler to the lumen 20f. In
some embodiments, the oxygen port includes a plug and/or membrane
formed of silicone, ePTFE or other polymer known to increase oxygen
diffusion. In other embodiments, the enrichment body 20p includes
an "oxygen capacitor" configured to absorb oxygen when the oxygen
concentration (e.g., around the sensor) is high, and to release the
absorbed (e.g., stored) oxygen when the oxygen concentration is
low. For example, in some embodiments, the infusion solution is
oxygenated, such that as the infusion solution flows through the
fluid coupler and/or catheter and contacts the oxygen capacitor,
the capacitor absorbs at least some of the oxygen present in the
solution. Then, when blood is drawn back and contacts the
capacitor, at least some of the oxygen stored in the capacitor
diffuses into the blood. For example, in some embodiments, the
oxygen capacitor is an oxygen-absorbing and oxygen-releasing
polymer applied to the lumenal surface of the fluid coupler and/or
catheter. In other embodiments, the oxygen capacitor is a membrane
or plug attached to the lumenal surface of the catheter and/or
fluid coupler. In yet another embodiment, the enrichment body is
inserted into the lumen of the fluid coupler and/or catheter
hub.
[0392] FIG. 1L illustrated an embodiment similar to that of FIG.
1K, except that at least a portion of the sensor 14 extends toward
the fluid coupler's 20 second side 20b. In some embodiments, the
sensor tip extends to the fluid coupler's second orifice 20i, but
not there past. In other embodiments, the sensor is configured to
extend into connected tubing. Accordingly, in this embodiment, the
sensor's electroactive surface(s) can be located at any point along
the length of the fluid coupler's lumen 20f.
[0393] FIG. 1M illustrates yet another embodiment of an analyte
sensor incorporated into a fluid coupler 20. In this embodiment, at
least one analyte sensor 14 is located on a support 20q that is
located on the lumenal surface of the fluid coupler. In some
embodiments, the support, including the at least one analyte sensor
located thereon, is inserted into the fluid coupler via an orifice
(e.g., 20i). In other embodiments, the fluid coupler includes a
port (e.g., an orifice, hole or opening, not shown) configured and
arranged to receive the support (e.g., the port and the support are
configured to mate with each other), such as via insertion through
the wall of the fluid coupler. In some embodiments, the at least
one analyte sensor comprises two or more analyte sensors, wherein
the analyte sensors are configured to detect one or more analytes.
In some embodiments, the at least one analyte sensor comprises 3,
4, 5, 6, 7, 8, 9, 10 or more analytes sensors. In some embodiments,
the at least one analyte sensor comprises a plurality of
micro-fabricated sensors, such as but not limited to a sensor
array. The sensor(s) can be applied to and/or deposited on the
support using any method known in the art, such as but not limited
to thin and/or thin film techniques, printing, plating, and the
like. In some embodiments, an analyte sensor is configured to
intersect the support, such as described with reference to FIGS.
2M-2Q. In some embodiments, the sensor (e.g., working electrode) is
substantially flush with the support, similar to the manner of some
glucose test strips that have electrodes printed on a planar
support using thin and/or thick film techniques. In some
embodiments, the sensor (e.g., working electrode) is at least
partially embedded in the support. For example, the working
electrode material can be deposited in a groove or well located on
the support. In preferred embodiments, the support is manufactured
from a polymer. Preferably, the polymer is configured for
malleability during manufacture but also provides sufficient
strength to function as a side of the fluid coupler. In other
embodiments, the support is formed from a metal, a ceramic or
glass. The support can have any shape, such as a planar or
non-planar shape. In some embodiments, the support has a planar
lumenal surface (e.g., the surface of the support that faces the
lumen of the fluid coupler). However, in other embodiments, the
support's lumenal surface is curved. In some embodiments, the
support (e.g., with sensor(s) applied thereto) is received into a
port. In some embodiments, the support makes a friction fit into
the port. In other embodiments, the support and port are configured
for a snap fit of the support into the port. In some embodiments,
the support can be secured into the port with an adhesive, hooks,
pins, and/or via welding. In other embodiments, the support
(including one or more analyte sensors) is inserted into the lumen
of the fluid coupler. For example, in one embodiment, the fluid
coupler does not include a port; rather the support (e.g.,
including sensors) is inserted through one of the fluid coupler's
orifices, such that the support is located adjacent to and/or on
the fluid coupler's lumenal surface. In a further embodiment, the
support is configured to conform to the lumenal surface of the
fluid coupler. In some embodiments, the support is attached to the
lumenal surface of the fluid coupler, such as with adhesive or
welding. In some embodiments, a catheter hub includes a port
configured for receipt of the support. Advantageously,
manufacturing the sensor(s) on a support and then integrating them
with the fluid coupler simplify manufacturing and reduce costs by
enabling high through put, automated manufacturing methods.
Additionally, a wider array of sensors and custom-order sensors can
be easily manufactured (e.g., as "panels" of sensors that test a
panel of analytes) and subsequently integrated into the fluid
couplers and/or catheter hubs. For example, in one embodiment
cassettes of sensors are manufactured in an automated reel-to-reel
process wherein sensor panels (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 13, 14, 15, 16, 17, 18, 19 or 20 or more sensors) are applied
to a continuous roll of polymer material (e.g., the support),
wherein the individual sensor cassettes are subsequently cut out of
the roll, such as using a die. In a second automated process, the
completed sensor cassettes are installed into the ports of
separately manufactured fluid couplers. Sensor electronics, such as
a PCB and electronic connectors are applied in yet another
automated process. In some embodiments, 2, 3, 4, 5, or more
different types of sensor cassettes (e.g., each type of sensor
cassette includes a different panel of analyte sensors) can be
manufactured (e.g., simultaneously on separate manufacturing lines
or on a single line at different times) and then subsequently
integrated into separately manufactured fluid couplers. In other
embodiments, for fluid couplers and/or catheters hubs having
different configurations, each configuration includes a port
configured to receive a single size and/or shape of sensor
cassette, wherein the size and/or shape of the cassette is
associated with a fluid coupler or catheter configuration. In some
embodiments, each type of sensor cassette (e.g., analyte panel)
includes a unique shape, such that it must be received by a port
configured to mate with it, similar to an interlocking lock and
key, such that certain cassettes are used with certain fluid
couplers and/or catheters. In some embodiments, certain
interlocking cassette and port configurations are associated with a
particular panel of analytes and/or a client. In yet another
embodiment, the sensor cassettes are configured to be replaceable
prior-to and/or during use. For example, in one embodiment, the
fluid coupler is provided with two or more types of cassettes
(e.g., different panels), such that the user inserts a selected
cassette into the fluid coupler's port prior to use. In an
alternative embodiment, the fluid coupler can be provided with two
or more cassettes of the same type, such that the cassette can be
changed out during use. For example, if a sensor on a first
cassette fails, the cassette can be replaced with a second cassette
of the same type. Analyte sensors and manufacturing methods
suitable for use with these embodiments can be found in U.S. Pat.
Nos. 5,108,819, 5,178,957, 5,879,828, 6,175,752, 6,284,478,
6,329,161, 6,565,509, 6,990,366, 6,134,461, 7,003,336, 6,784,274,
6,103,033, and 5,899,855, each of which is incorporated herein by
reference in its entirety.
[0394] FIGS. 2A to 2B illustrate one exemplary embodiment of an
analyte sensor integrally formed on a catheter. The system 210 is
configured to measure an analyte and generally includes a catheter
212 configured for insertion into a host's blood stream (e.g., via
a vein or artery) and a sensor at least partially integrally formed
on the catheter's exterior surface 232. Preferably, the sensor 214
includes at least one exposed electroactive area 240 (e.g., a
working electrode), a membrane system (e.g., including an enzyme),
a reference electrode (proximal to or remote from the working
electrode), and an insulator.
[0395] In this embodiment, the catheter includes a lumen 212a and
an orifice 212b at its proximal end, for providing fluid connection
from the catheter's lumen to the host's blood stream (see FIG.
2A).
[0396] In some embodiments, the catheter is inserted into a vein,
as described elsewhere herein. In other embodiments, the catheter
is inserted into an artery, as described elsewhere herein. The
catheter can be any type of venous or arterial catheter commonly
used in the art (e.g., peripheral catheter, central catheter,
Swan-Gantz catheter, etc.). The catheter can be made of any useful
medical grade material (e.g., polymers and/or glass) and can be of
any size, such as but not limited to from about 1 French (0.33 mm)
or less to about 30 French (10 mm) or more; for example, 2, 3, 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 French
(3 French is equivalent to about 1 mm). In some embodiments, the
catheter is configured and arranged for insertion into neonatal or
other pediatric hosts (e.g., 22-24 gauge or smaller). In certain
embodiments, the catheter can be a single lumen catheter or a
multi-lumen catheter. In some embodiments, the catheter can include
one or more perforations, to allow the passage of host fluid
through the lumen of the catheter. In one embodiment, the catheter
is a dual-lumen catheter wherein a first lumen is configured to
receive an analyte sensor and a second lumen is configured for
fluid infusion. In preferred embodiments, the catheter is
configured such that the orifice of the first lumen is sufficiently
proximal to connector (of the catheter) relative to the orifice of
the second lumen, that samples drawn back into the first lumen
(e.g., to be tested by the analyte sensor) are substantially
undiluted by the infused fluid.
[0397] At its distal end 212c, the catheter 212 includes (e.g., in
fluid communication) a connector 218. The connector can be of any
known type, such as a Leur lock, a T-connector, a Y-connector, a
cross-connector or a custom configuration, for example. In some
embodiments, the connector includes at least one valve. At a second
side 218e (e.g., back end), the connector 218 can be operatively
connected to a saline system (e.g., saline bag and tubing), other
medical devices (e.g., automatic blood chemistry machine, dialysis
machine, a blood bag for collecting donated blood, etc.), or
capped.
[0398] In some embodiments, the system 210 includes sensor
electronics (not shown) operatively connected to the analyte
sensor, wherein the sensor electronics are generally configured to
measure and/or process the sensor data as described in more detail
elsewhere herein. In some embodiments, the sensor electronics can
be partially or wholly disposed with (e.g., integral with, disposed
on, or proximal to) the connector 218 at the distal end of the
catheter or partially or wholly remote from the catheter (e.g., on
a stand or on the bedside). In one embodiment, the sensor
electronics disposed with the connector include a potentiostat. In
some embodiments, the sensor electronics are configured to measure
the host's analyte concentration substantially continuously. For
example, the sensor can measure the analyte concentration
continuously or at time intervals ranging from fractions of a
second up to, for example, 1, 2, or 5 minutes or longer.
[0399] FIGS. 2C to 2F illustrate additional embodiments of the
sensor shown in FIGS. 2A to 2B. The catheter 212 is shown with an
integral sensor 214 having at least one electrode 240 formed on its
exterior surface 232 (e.g., FIG. 2F). In general, the sensor can be
designed with 1, 2, 3, 4 or more electrodes and can be connected by
traces (or the like) to electrical contacts 218d (or the like) at
the second end of the connector 218 (e.g., FIGS. 2A to 2F). In some
embodiments, the sensor is hard-wired to the sensor electronics;
alternatively, any operable connection can be used. Preferably, the
sensor includes at least one working electrode and at least one
reference or counter electrode. In some embodiments, the reference
electrode is located proximal to the at least one working electrode
(e.g., adjacent to or near to the working electrode). In some
alternative embodiments, the reference electrode is located
remotely from the working electrode (e.g., away from the working
electrode, such as but not limited to within the lumen of the
catheter 212 (or connector 218), on the exterior of the sensor
system, in contact with the patient (e.g., on the skin), or the
like). In some embodiments, the reference electrode is located
proximal to or within the fluid connector, such as but not limited
to, coiled about the catheter adjacent to the fluid connector or
coiled within the fluid connector and in contact with fluid flowing
through the fluid coupler, such as saline or blood. In some
embodiments, the sensor can also include one or more additional
working electrodes (e.g., for measuring baseline, for measuring a
second analyte, or for measuring a substantially non-analyte
related signal, and the like, such as described in more detail in
U.S. Patent Publication No. US-2005-0143635-A1 and U.S. Patent
Publication No. US-2007-0027385-A1, which are incorporated herein
by reference in their entirety. In some embodiments one or more
counter electrodes can be provided on a surface of the catheter or
within or on the fluid connector.
[0400] In some of the preferred embodiments, the catheter is
designed to indwell within a host's blood flow (e.g., a peripheral
vein or artery) and remain in the blood flow for a period of time
(e.g., the catheter is not immediately removed). In some
embodiments, the indwelling catheter can be inserted into the blood
flow for example, for a few minutes or more, or from about 1 to 24
hours, or from about 1 to 10 days, or even longer. For example, the
catheter can indwell in the host's blood stream during an entire
perioperative period (e.g., from host admittance, through an
operation, and to release from the hospital).
[0401] In some embodiments, the catheter is configured as an
intravenous catheter (e.g., configured to be inserted into a vein).
The catheter can be inserted into any commonly used vein, such as
in a peripheral vein (e.g., one of the metacarpal veins of the
arm); in some embodiments (e.g., such as described with reference
to FIGS. 1A to 1E) the analyte sensor inserted into a catheter. In
alternative embodiments, the sensor is integrally formed on a
catheter such as described in more detail with reference to FIGS.
2A to 2F, for example. Other veins, such as leg or foot veins, hand
veins, or even scalp or umbilical veins, can also be used.
[0402] In addition to sensing analyte levels via a sensor system as
described herein, the intravenous catheter can be used for delivery
of fluids and/or drugs to the host's circulatory system. The
catheter can be configured to be coupled to other medical devices
or functions, for example, saline, blood products, total parenteral
feeding or medications can be given to the host via the indwelling
intravenous catheter. In some embodiments, the catheter can be
operatively connected to a pump, such as an infusion pump, to
facilitate flow of the fluids into the host and a desired rate. For
example, an infusion pump can pump saline into the host at a rate
of 1 cc per minute, or at higher or lower rates. The rate of
infusion can be changed (increased or decreased). For example, an
infusion can be temporarily stopped, to permit injection of pain
medication into the IV system, followed by increasing the infusion
rate (e.g., for 5 minutes) to rapidly deliver the pain medication
to the host's circulatory system.
[0403] In some embodiments, the catheter is configured as an
arterial catheter (e.g., configured to be inserted into an arterial
line or as part of an arterial line). Typically, an arterial
catheter is inserted in the wrist (radial artery), armpit (axillary
artery), groin (femoral artery), or foot (pedal artery). Generally,
arterial catheters provide access to the host's blood stream
(arterial side) for removal of blood samples and/or application of
test devices, such as but not limited to a pressure transducer (for
measuring blood pressure automatically), however, arterial
catheters can also be used for delivery of fluids or medications.
In one embodiment, a catheter is inserted into an arterial line and
the sensor inserted into the catheter (e.g., functionally coupled)
as described elsewhere herein. Saline filled non-compressible
tubing is then coupled to the sensor, followed by a pressure
transducer. An automatic flushing system (e.g., saline) is coupled
to the tubing as well as a pressure bag to provide the necessary
pressure. Electronics are generally operatively coupled to the
pressure transducer for calculating and displaying a variety of
parameters including blood pressure. Other medical devices can also
be connected to the arterial catheter, to measure various blood
components, such as but not limited to O.sub.2, CO.sub.2,
PCO.sub.2, PO.sub.2, potassium, sodium, pH, lactate, urea,
bilirubin, creatinine, hematocrit, various minerals, various
metabolites, and the like.
[0404] In another embodiment, a blood pressure measurement system
is inserted into the host and can be used as is known in the art.
The analyte sensor (e.g., glucose sensor), such as the embodiment
shown in FIGS. 1A-1E, is inserted into the pre-inserted (e.g.,
already in-dwelling) catheter using the following general
methodology. First, the pressure transducer is temporarily disabled
by disconnecting from the pre-inserted catheter. A cap (optionally)
covers the protective slotted sheath and can be removed so as to
enable the sensor to be grasped at the fluid coupler. The sheath,
which is generally more rigid than the sensor but less flexible
than a needle, is then threaded through the pre-inserted catheter
so as to extend beyond the catheter into the blood stream (e.g., by
about 0.001 inches to about 1 inches). The sheath is then removed
by sliding the sensor through a small outlet hole and/or slot in
the sheath. Thus, the sensor remains within the pre-inserted
catheter and the fluid coupler, which supports the distal portion
of the sensor, is coupled to the catheter itself. Saline filled
non-compressible tubing is then coupled to the second side (e.g.,
back end) of the fluid coupler. The sensor electronics (whether
adjacent to the fluid coupler or otherwise wired to the fluid
coupler) are then operatively connected (e.g., wired or wirelessly)
to the sensor to initiate sensor function.
[0405] In some embodiments, a portion of the sensor system (e.g.,
sensor, catheter, or other component) can be configured to allow
removal of blood samples from the host's blood stream (e.g., artery
or vein). Sample removal can be done using any systems and methods
known in the art, for example, as is practiced for removing a blood
sample from an arterial catheter (e.g., and arterial line). In one
such exemplary embodiment, any tubing or equipment coupled to the
second side of the fluid coupler is disconnected. A syringe is then
be coupled to the second side and blood removed via the catheter by
pulling back on the syringe plunger. In a further embodiment,
saline can be flushed through the fluid coupler and catheter. In
another embodiment, the fluid coupler can be configured with a side
valve, to allow coupling of a syringe, for removal of blood samples
or delivery of fluids, such as medications, without disconnecting
attached tubing of equipment, and the like. In still another
embodiment, a valve or diaphragm, for access to the system by a
syringe, can be coupled into the tubing at a short distance from
the fluid coupler. In yet another embodiment, the sensor is
integrally formed on the arterial catheter, such as the embodiment
shown in FIGS. 2A-2B, and tubing can be disconnected from the
connector, a syringe operably associated with the connector, and
blood removed with the syringe. After blood collection, the syringe
is removed and the tubing reconnected to the connector.
[0406] In still another embodiment, the analyte sensor can be
functionally coupled to an extracorporeal blood flow device. A
variety of devices exist for testing various blood properties
and/or analytes at the bedside, such as but not limited to the
blood gas and chemistry devices manufactured by Via Medical,
Austin, Tex., USA. These devices generally withdraw a blood sample
from the host, test the blood sample, and then return it to the
host. Such a device can be connected in series to the arterial
catheter, with the sensor in-between, and using systems and methods
known in the art. In one embodiment, a sensor, such as the
embodiment shown in FIGS. 1A-1E, is functionally connected to an
in-dwelling arterial catheter, as described herein, and the
extracorporeal blood flow device is connected to the second side of
the fluid coupler. In an alternative embodiment, the sensor is
integrally formed on the arterial catheter, such as the embodiment
shown in FIGS. 2A-2F, and the extracorporeal blood flow device is
functionally connected to the connector 218. Other devices, such as
but not limited to dialysis machines, heart-lung bypass machines or
blood collection bags, or other vascular access devices, can be
functionally coupled to the analyte sensor.
[0407] The analyte sensor system of the preferred embodiments can
be designed with a variety of alternative configurations. In some
embodiments, the sensor is connected to a fluid connection device.
The fluid connection device in these embodiments can be any
standard fluid connection device known in the art, such as a fluid
coupler, or a fluid coupler custom manufactured to preferred
specifications. On its first side, the fluid coupler is configured
to couple to an existing catheter or cannula (as described with
reference to FIGS. 1A-1E). The catheter (or cannula) is typically
inserted into a vascular access device and/or into a hospital host
during a hospital stay. For example, the catheter can be inserted
into an arterial line (e.g., for removing blood samples or for
measuring blood pressure using a pressure transducer) or a venous
line (e.g., for intravenous delivery of drugs and other fluids). In
general practice, the catheter is inserted into the host's blood
vessel, for example, and maintained there for a period of time
during the host's hospital stay, such as part of the stay or during
the entire stay (e.g., perioperatively). In one alternative
embodiment, another vascular access device (e.g., other than a
catheter) can be used to receive the sensor. In yet another
alternative embodiment, the sensor system of the preferred
embodiments can be inserted into a vascular access device (e.g.,
rather than the vascular system directly). Some examples of
vascular access devices include but are not limited to, catheters,
shunts, automated blood withdrawal devices and the like.
[0408] In some embodiments, such as the embodiment illustrated in
FIGS. 1A to 1E, the system 10 is configured such that the sensor is
inserted into a vascular access device, such as but not limited to
a catheter 12 (e.g., a catheter that has been inserted into the
host's blood stream prior to sensor insertion). In general,
catheters are small, flexible tubes (e.g., soft catheter) but they
can also be larger, rigid tubes. Catheters are inserted into a
host's body cavity, vessel, or duct to provide access for fluid
removal or insertion, or for access to medical equipment. Catheters
can also be inserted into extracorporeal devices, such as but not
limed to an arterio-venous shunt for the transfer of blood from an
artery to a vein. Some catheters are used to direct access to the
circulatory system (e.g., venous or arterial catheters, Swan Gantz
catheters) to allow removal of blood samples, the infusion of
fluids (e.g., saline, medications, blood or total parenteral
feeding) or access by medical devices (e.g., stents, extracorporeal
blood chemistry analysis devices, invasive blood pressure monitors,
etc.).
[0409] Preferably, the sensor is designed to include a protective
cap, as illustrated in FIGS. 1A-1E. Namely, FIGS. 1A and 1B
illustrates the catheter (the catheter cap having been removed
prior to insertion), well known to those skilled in the art, which
can be inserted into the host's blood vessel using standard
methods. The sensor 14 is configured for measurement of an analyte
(e.g., glucose) in the host's body, and is in fluid connection
within the catheter lumen, which is in fluid connection with the
fluid coupler 20 of the sensor. The first side 20a of the fluid
coupler 20 of the sensor is designed to couple to the catheter,
e.g., by screwing or snapping thereon, and can also couple (on its
second side 20b) with other medical devices. One advantage of the
fluid coupler is that it provides for a small amount of bleed back,
to prevent air bubbles in the host's blood stream.
[0410] The exemplary sensor system 10 of FIGS. 1A and 1B further
includes a slotted protective sheath 26 that supports and protects
the sensor during sensor insertion, for example, the sheath
increases the sensor visibility (e.g., the sensor is so thin that
it can be difficult for some people to see without the protective
sheath) and provides for ease of sliding the sensor into the
catheter. The slotted protective sheath is configured to fit within
the fluid coupler and houses the sensor during insertion of the
sensor into the catheter (e.g., an indwelling catheter within the
host's blood flow). Preferably, the protective sheath is
substantially more rigid than the sensor and at the same time
substantially more flexible that a standard syringe needle, however
other designs are possible. To facilitate removal of the protective
sheath, a slot 30 is provided with an optional outlet hole 30a,
which is described in more detail with reference to FIG. 1C, and a
hub 28. By grasping and pulling the hub, the user (e.g., health
care professional) can withdraw the protective sheath after
coupling the fluid coupler to the catheter. Prior to insertion of
the sensor, a cap is provided, to cover the protective sheath, for
example, to keep the sheath and sensor sterile, and to prevent
damage to the components during shipping and/or handling.
[0411] In general, the sensor system is configured with a
potentiostat and/or sensor electronics that are operatively coupled
to the sensor. In some embodiments, a portion of the sensor
electronics, such as the potentiostat, can be disposed directly on
the fluid coupler. However, some or all of the sensor electronics
(including the potentiostat) can be disposed remotely from the
fluid coupler (e.g., on the bedside or on a stand) and can be
functionally coupled (e.g., wired or wireless), as is generally
known to those skilled in the art.
[0412] FIGS. 1C1 and 1C2 are cross-sectional views (not to scale)
of the fluid coupler, including a protective sheath 26, a sensor
14, and a cap 32 (cap to be removed prior to insertion) in one
embodiment. The protective sheath 26 extends through the fluid
coupler and houses the sensor, for sensor insertion into a
catheter. The protective sheath includes an optional outlet hole
30a, through which the sensor extends and a slot 30 along a length
of the protective sheath that communicates with the outlet hole and
enables the protective sheath to be removed after the sensor has
been inserted into the host's body. The protective sheath includes
a hub 28 for ease of handling.
[0413] In some embodiments, the glucose sensor is utilized in
combination with another medical device (e.g., a medical device or
access port that is already coupled to, applied to, or connected to
the host) in a hospital or similar clinical setting. For example, a
catheter can be inserted into the host's vein or artery, wherein
the catheter can is connected to additional medical equipment. In
an alternative example, the catheter is placed in the host to
provide quick access to the host's circulatory system (in the event
of a need arising) and is simply capped. In another example, a
dialysis machine can be connected to the host's circulatory system.
In another example, a central line can be connected to the host,
for insertion of medical equipment at the heart (e.g., the medical
equipment reaches the heart through the vascular system, from a
peripheral location such as a leg or arm pit).
[0414] In practice of coupling to a catheter, before insertion of
the sensor, the access port is opened. In one exemplary embodiment
of a pre-inserted catheter that is capped, the cap is removed and
the sensor inserted into the catheter. The back end of the sensor
system can be capped or attached to additional medical equipment
(e.g., saline drip, blood pressure transducer, dialysis machine,
blood chemistry analysis device, etc.). In another exemplary
embodiment, medical equipment (e.g., saline drip, blood pressure
transducer, dialysis machine, blood chemistry analysis device,
etc.) is already connected to the catheter. The medical equipment
is disconnected from the catheter, the sensor inserted into (and
coupled to) the catheter and then the medical equipment reconnected
(e.g., coupled to the back end of the sensor system).
[0415] In some embodiments, the sensor is inserted directly into
the host's circulatory system without a catheter or other medical
device. In one such exemplary embodiment, the sheath covering the
sensor is relatively rigid and supports the sensor during
insertion. After the sensor has been inserted into the host's vein
or artery, the supportive sheath is removed, leaving the exposed
sensor in the host's vein or artery. In an alternative example, the
sensor is inserted into a vascular access device (e.g., with or
without a catheter) and the sheath removed, to leave the sensor in
the host's vein or artery (e.g., through the vascular access
device).
[0416] In various embodiments, in practice, prior to insertion, the
cap 32 over the protective sheath is removed as the health care
professional holds the glucose sensor by the fluid coupler 20. The
protective sheath 26, which is generally more rigid than the sensor
but more flexible than a needle, is then threaded through the
catheter so as to extend beyond the catheter into the blood flow
(e.g., by about 0.010 inches to about 1 inches). The protective
sheath is then removed by sliding the sensor through the (optional)
outlet hole 30a and slotted portion 30 of the sheath (e.g., by
withdrawing the protective sheath by pulling the hub 28). Thus the
sensor remains within the catheter; and the fluid coupler 20, which
holds the sensor 14, is coupled to the catheter itself (via its
connector 18). Other medical devices can be coupled to the second
side of the fluid coupler as desired. The sensor electronics (e.g.,
adjacent to the fluid coupler or otherwise coupled to the fluid
coupler) are then operatively connected (e.g., wired or wirelessly)
to the sensor for proper sensor function as is known in the
art.
[0417] In another embodiment, the catheter 12 includes a plurality
of perforations (e.g., holes) that allow the host's fluid (e.g.,
blood) to flow through the lumen 12a of the catheter. The fluid
flowing through the catheter can make contact with a sensor 14
inserted therein. In a further embodiment, the sensor does not
protrude out of the catheter's tip 12b and the host's blood flowing
through the perforated catheter's lumen contacts the sensor's
electroactive surfaces.
[0418] In still another embodiment, the catheter 12 includes at
least a first lumen and a second lumen. The sensor 14 is configured
for insertion into the catheter's first lumen. The second lumen can
be used for infusions into the host's circulatory system or sample
removal without disturbing the sensor within the first lumen.
[0419] FIGS. 2A-2F are schematic views of a sensor integrally
formed (integrally incorporated) onto a surface of a catheter, in
some exemplary embodiments. In some embodiments, the sensor can be
integrally formed on an exterior surface 232 of the catheter. In
other embodiments, the sensor can be integrally formed on an
interior surface of the catheter (e.g., on a lumenal surface). In
still other embodiments, the sensor can be integrally formed on the
sensor's tip (e.g., as indicated by 214a). In yet other
embodiments, the sensor can be integrally incorporated with the
catheter, for example by bonding a sensor of the type described in
FIGS. 3A to 3C into an inner or outer surface of the catheter.
[0420] In some embodiments, one or more of the electrodes is
deposited on the in vivo portion of the catheter 212, such as via
screen-printing and/or electrospinning. In some embodiments, at
least one of the electrodes 240, such as but not limited to a
counter and/or a reference electrode is deposited within the ex
vivo portion of the catheter (e.g., within the connector/hub). In
one embodiment, two working electrodes 240 are disposed on the
exterior surface 232 of the catheter's in vivo portion. The first
working electrode is configured to generate a signal associated
with the analyte and with non-analyte-related species that have an
oxidation/reduction potential that overlaps with that of the
analyte. The second working electrode is configured to generate a
signal associated with non-analyte-related species that have an
oxidation/reduction potential that overlaps with that of the
analyte. As described elsewhere herein, the signals of the first
and second working electrodes can be processed to provide a
substantially analyte-only signal. Continuous analyte sensors
including two working electrodes are described in greater detail
elsewhere herein, in U.S. Patent Publication No.
US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1,
U.S. Patent Publication No. US-2007-0027284-A1, U.S. Patent
Publication No. US-2007-0032717-A1, U.S. Patent Publication No.
US-2007-0093704-A1, and U.S. Patent Publication No.
US-2008-0083617-A1, each of which is incorporated herein by
reference in its entirety.
[0421] In some alternative embodiments, one or more analyte sensors
are disposed (e.g., deposited, formed) on the exterior surface of
the in vivo portion of the catheter. Each sensor can include one,
two or more working electrodes. The electrodes can be configured as
described elsewhere therein. In some embodiments, the catheter 12
is configured with two or more analyte sensors, wherein each of the
sensors is configured to detect a different analyte and/or a
property of the sample, as described elsewhere herein. For example,
in some embodiments, the sensors are configured to detect at least
two analytes such as but not limited to albumin, alkaline
phosphatase, alanine transaminase, aspartate aminotransferase,
bilirubin, blood urea nitrogen, calcium, CO.sub.2, chloride,
creatinine, glucose, gamma-glutamyl transpeptidase, hematocrit,
lactate, lactate dehydrogenase, magnesium, oxygen, pH, phosphorus,
potassium, sodium, total protein, uric acid, a metabolic marker,
various drugs, various minerals, various metabolites, and the like.
In some embodiments, at least one of the sensors is configured to
detect a property of the host's blood, such as but not limited to
pH, oxygen tension, PCO.sub.2, PO.sub.2, temperature, hematocrit,
and the like. In some circumstances, one or more of the plurality
of analyte sensor can be configured as a back-up or redundant
sensor to a first sensor, such as to confirm the correct
functioning of the first sensor. For example, two glucose sensors
could be disposed within the connector, such that the second
glucose sensor provides a confirmation of the first glucose
sensor's measurements.
[0422] Generally, the sensor system is provided with a cap 32 that
covers the catheter and the in vivo portion of the integral sensor
(e.g., see FIG. 1C.sub.2). A needle or trochar that runs the length
of the catheter supports the device during insertion into the
host's blood stream. Prior to use, medical caregiver holds the
device by the fluid connector 218 and removes the cap to expose the
in vivo portion of the device (e.g., the catheter). The caregiver
inserts the in vivo portion of the device into one of the host's
veins or arteries (depending upon whether the catheter is an
intravenous catheter or an arterial catheter). After insertion, the
needle is withdrawn from the device. The device is then capped or
connected to other medical equipment (e.g., saline bag, pressure
transducer, blood collection bag, total parenteral feeding,
dialysis equipment, automated blood chemistry equipment, etc.). In
some alternative embodiments, the sensor-integrated catheter can be
in communication (e.g., fluid communication) with the host's
vascular system through a vascular access device.
[0423] In some embodiments, an analyte sensor system includes a
sensing mechanism substantially similar to that described in U.S.
Patent Publication No. US-2006-0020187-A1, which is incorporated
herein by reference in its entirety; for example, with platinum
working electrode and silver reference electrode coiled there
around. Alternatively, the reference electrode can be located
remote from the working electrode so as not to be inserted into the
host, and can be located, for example, within the fluid coupler 20,
thereby allowing a smaller footprint in the portion of the sensor
adapted for insertion into the body (e.g., blood stream); for
example, without a coiled or otherwise configured reference
electrode proximal to the working electrode. Although a platinum
working electrode is discussed, a variety of known working
electrode materials can be utilized (e.g., Platinum-Iridium or
Iridium). When located remotely, the reference electrode can be
located away from the working electrode (e.g., the electroactive
portion) at any location and with any configuration so as to
maintain bodily and/or in fluid communication therewith as is
appreciated by one skilled in the art.
[0424] In an alternative embodiment, the sensor tip 14a includes an
enlarged, atraumatic area, for example a dull or bulbous portion
about two times the diameter of the sensor or larger. In one
exemplary embodiment, the enlarged portion is created by heating,
welding, crushing or bonding a substantially rounded structure onto
the tip of the sensor (e.g., polymer or metal). In another
exemplary embodiment, the tip of the sensor is heated (e.g., arc
welded or flash-butt resistance welded) to cause the tip to enlarge
(e.g., by melting). The enlarged portion can be of any atraumatic
shape, such as but not limited to oval, round, cone-shaped,
cylindrical, teardrop, etc. While not wishing to be bound by
theory, it is believed that an atraumatic or enlarged area enables
enhanced stability of a small diameter sensor in the blood flow and
ensures that the sensor remains within the blood flow (e.g., to
avoid piercing a vessel wall and/or becoming inserted
subluminally.)
[0425] In some embodiments, one or more additional working
electrodes can be provided on the sensor for measuring baseline,
and thereby subtracting the baseline from the first working
electrode to obtain a glucose-only signal and/or to measure
additional analytes, as disclosed in copending U.S. Patent
Publication No. US-2005-0143635-A1, U.S. Patent Publication No.
US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1,
and U.S. Patent Publication No. US-2008-0083617-A1, all of which
are herein incorporated by reference in their entirety.
[0426] Referring now to FIGS. 2A-2E in more detail, some
embodiments of the analyte sensor system include a catheter 212
adapted for inserting into a host in a hospital or clinical
setting, wherein the analyte sensor 214 is built integrally with
the catheter 212. For example, a glucose sensor can be integrally
formed on the catheter itself. FIGS. 2A-2B illustrate one
embodiment, wherein the catheter 212 is configured both for
insertion into a host, and can be configured to couple to other
medical devices on its ex vivo end. However, coupling to other
medical devices is not necessary. In some embodiments, the catheter
includes a connector 218 configured for connection to tubing or
other medical devices, as described herein. The embodiment shown in
FIGS. 2A-2B includes two or three electrodes 240 on the outer
surface of the in vivo portion of the catheter 212. In some
embodiments, the catheter is perforated (as described elsewhere
herein) and at least one electrode is disposed within the lumen
(not shown) of the perforated catheter. In some embodiments, the
catheter includes a single lumen. In other embodiment, the catheter
includes two or more lumens.
[0427] With reference to FIGS. 2C-2E, in some embodiments, at least
one working electrode 240 is disposed on the exterior surface of
the in vivo portion of the catheter. Alternatively, the at least
one working electrode can be disposed on an interior surface of the
catheter, on the tip of the catheter, extend from the catheter, and
the like. In general, the preferred embodiments can be designed
with any number of electrodes, including one or more counter
electrodes, one or more reference electrodes, and/or one or more
auxiliary working electrodes. In further embodiments, the
electrodes can be of relatively larger or smaller surface area,
depending upon their uses. In one example, a sensor includes a
working electrode and a reference electrode that has a larger
surface area (relative to the surface area of the working
electrode) on the surface of the catheter. In another example, a
sensor includes a working electrode, a counter electrode, and a
reference electrode sized to have an increased surface area as
compared to the working and/or counter electrode. In some
embodiments, the reference electrode is disposed at a location
remote from the working electrode, such as within the connector
(e.g., coiled within the connector). In some embodiments, the
reference electrode is located on the host's body (e.g., in body
contact).
[0428] The electrodes 240 can be deposited on the catheter using
any suitable techniques known in the art, for example, thick or
thin film deposition techniques. The electrodes can be formed of
any advantageous electrode materials known in the art (e.g.,
platinum, platinum-iridium, palladium, graphite, gold, carbon,
silver, silver-silver chloride, conductive polymer, alloys,
combinations thereof, and the like). In other embodiments, one or
more of the electrodes is formed from an electrically conductive
material (e.g., wire or foil comprising platinum, platinum-iridium,
palladium, graphite, gold, carbon, silver, silver-silver chloride,
conductive polymer, alloys, combinations thereof, and the like)
applied to the exterior surface of the catheter, such as but not
limited twisting, coiling, rolling or adhering.
[0429] In some embodiments, the catheter is (wired or wirelessly)
connected to sensor electronics (not shown, disposed on the
catheter's connector and/or remote from the catheter) so as to
electrically connect the electrodes on the catheter with the sensor
electronics. The inserted catheter (including the sensor integrally
formed thereon) can be utilized by other medical devices for a
variety of functions (e.g., blood pressure monitor, drug delivery,
etc).
[0430] Referring now to FIGS. 2G through 2S, in some preferred
embodiments a plurality of analyte sensors 240 are disposed within
a widened portion of the catheter, such as but not limited to a
flared portion and/or a connector portion 212, or within the
interior of a connector 250, such as but not limited to a Leur
lock, a Y-connector, a T-connector, an X-connector, and a valve,
wherein a first side/end of the connector is configured to be
coupled and/or connected to another vascular access device, such as
a catheter or cannula, and a second side (e.g., end) of the
connector is configured to be coupled/connected to other IV
equipment, such as another connector, a valve, IV tubing, and the
like.
[0431] FIG. 2G is a cross section of a vascular access device
including a plurality of analyte sensors 240 in one embodiment. The
vascular access device, such as a catheter includes an in vivo
portion configured for insertion into a circulatory system of the
host, including a lumen 212a, and a connector 218 having a wall 260
defining a duct 218b. In some embodiments, an inner diameter of the
connector is greater than an inner diameter of the in vivo portion.
For example, in some embodiments, the vascular access device is a
20-gauge or smaller catheter. In some embodiments, the in vivo
portion of the catheter is configured and arranged for insertion
into a circulatory system of a pediatric host, such as but not
limited to a neonatal host. The vascular access device is
configured and arranged for receipt of a sample of a bodily fluid
of a host (e.g., blood after catheter insertion). At the proximal
end, also referred to herein as the in vivo portion, the vascular
access device includes a catheter 212 having a lumen 212a and a
small orifice 212b. At the distal end, also referred to here as the
ex vivo portion, the vascular access device includes a connector
218, also referred to herein as the "hub." The hub includes an
orifice 218c, which is configured for connection (e.g., fluid
communication) with other IV equipment, such as via one or more
flanges 218a. The connector 218 also includes a duct 218b, also
referred to a widened portion (as compared to lumen 212a, which may
be referred to as the connector's lumen. A plurality of analyte
sensors 240 is disposed within the duct 218b. In some embodiments,
the device includes an analyte sensor 240, wherein at least a
portion of the analyte sensor is located in the lumen or duct, such
that the analyte sensor is located within about 60, 55, 50, 45, 40,
35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or less from a source
of the biological sample. For example, in some embodiments, the
electroactive surfaces are within about 40-mm or less of the blood
prior to drawing the blood back into the hub of an implanted
catheter or into a fluid coupler connected to an implanted
catheter. In some embodiments, the analyte sensor is located within
about 30-mm or less from a source of the sample. Configuring the
system such that the analyte sensor(s) (e.g., the electroactive
surfaces of the electrodes) are located within only 60-mm or less
from the sample (e.g., prior to drawing back the sample into the
catheter) translates into a requirement for only very small sample
volumes. For example, in some embodiments, the device is configured
such that the analyte sensor is bathed in the sample when (no more
than) about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50,
25, 15, 10, or 5-.mu.l or less of the bodily fluid (e.g., blood) is
drawn back. In some embodiments, one or more of the analyte sensors
240 is deposited and/or formed on a surface of the duct 218b, such
as by screen printing or other useful deposition techniques. In
some embodiments, one or more of the analyte sensors 240 is applied
to the duct's surface, such as by adhering or micro welding a
previously formed sensor to the duct's surface. In some
embodiments, at least a portion of one or more of the analyte
sensors 240 is unattached to the duct's surface. The analyte
sensors can be configured to detect one or more analytes using any
means known in the art, such as but not limited to electrochemical
detection, enzymatic detection, chemical detection, physical
detection, immunochemical detection, optical detection, radiometric
detection, and combinations thereof. For example, in one embodiment
of a device including three sensors 240 within the hub 218, a first
sensor 240 is configured to detect glucose electrochemically, a
second sensor 240 is configured to detect oxygen optically, and the
third sensor 240 is configured to detect bilirubin
immunochemically.
[0432] In one exemplary embodiment, a system configured to measure
one or more analytes in a host is provided, wherein the system
includes a vascular access device including a first portion
configured for insertion into a host and a second portion
configured to remain outside the host after insertion of the first
portion; at least one analyte sensor 240 located within the second
portion of the vascular access device, such that the at least one
analyte sensor is exposed to a biological sample when the
biological sample is drawn back about 40-mm or less, when the
vascular access device is in fluid communication with a circulatory
system of the host; and a flow control device configured to
regulate exposure of the at least one sensor to a biological sample
and to a reference solution according to a flow profile. In some
embodiments, the system is configured such that the at least one
analyte sensor is exposed to the biological sample when about
300-.mu.l or less of the biological sample is drawn back. In
another embodiment, the system is configured such that the at least
one analyte sensor is exposed to the biological sample when about
200-.mu.l or less of the biological sample is drawn back. In some
embodiments, the vascular access device includes a catheter. For
example, in some embodiments, the catheter is 22-gauge or smaller.
In some embodiments, a lumen of the second portion is wider than a
lumen of the first portion. For example, the lumen (e.g., duct) of
a catheter hub is wider than the lumen of the in vivo portion of
the catheter, in exemplary embodiments. In some embodiments, the
second portion includes a connecting end on the catheter. For
example, the second end of the catheter (e.g., the hub) is
configured and arranged for connection to tubing (e.g., IV tubing,
the tubing assembly). In other embodiments, the second portion
includes a fluid coupler, wherein the fluid coupler is configured
to releasably mate with a catheter. In some embodiments, the at
least one sensor is incorporated into the second portion (e.g., the
ex vivo portion of the catheter), such as on an inner surface of
the second portion. In some embodiments, at least a portion of the
at least one sensor is disposed in an orientation substantially
parallel to a longitudinal axis of the second portion. In some
embodiments, at least a portion of the at least one sensor is
disposed in an orientation substantially perpendicular to a
longitudinal axis of the second portion. In some embodiments, the
at least one sensor includes an exposed electroactive surface area
with a dimension substantially equal to a width of a lumen of the
second portion. In some embodiments, the exposed electroactive
surface area intersects the lumen of the second portion. In some
embodiments, the at least one analyte sensor includes at least
three analyte sensors located within the second portion of the
catheter. In a further embodiment, the at least one analyte sensor
includes at least eight analyte sensors located within the second
portion of the catheter. In some embodiments, the second portion is
configured to provide identification information associated with a
flow profile, such as described elsewhere herein. In some
embodiments, the system is configured to program the flow profile
(of a flow control device) in response to automatic receipt of the
identification information. In some embodiments, the identification
information is provided by a mechanical structure of the second
portion (e.g., the catheter). In some embodiments, the
identification information is provided by electronics of the second
portion (e.g., the catheter).
[0433] In another exemplary embodiment, a system configured to
measure one or more analytes in a host is provided, wherein the
system includes a fluid coupler including a first end and a second
end, wherein the first end is configured to releasably mate with a
connecting end of a catheter, and wherein the second end is
configured to releasably mate with a tubing assembly; and at least
one analyte sensor located within the fluid coupler such that when
the fluid coupler is mated to a catheter inserted into a
circulatory system of a host, the at least one analyte sensor is
exposed to a biological sample when the biological sample is drawn
back about 40-mm or less. In one embodiment, the at least one
sensor is located on an inner surface of the fluid coupler. In some
embodiments, the at least one sensor is incorporated into the fluid
coupler. In a further embodiment, the at least one sensor is
disposed within a lumen of the fluid coupler (e.g., the second
portion). In some embodiments, the system is configured such that
the at least one analyte sensor is exposed to the biological sample
when about 300-.mu.l or less of the biological sample is drawn
back. In another embodiment, the system is configured such that the
at least one analyte sensor is exposed to the biological sample
when about 200-.mu.l or less of the biological sample is drawn
back. In some embodiments, the at least one sensor is incorporated
into the fluid coupler. In some embodiments, the at least one
sensor is located on an inner surface of the fluid coupler. In some
embodiments, the at least one sensor is disposed within a lumen of
the fluid coupler. The at least one analyte sensor can be disposed
in an orientation substantially parallel to a longitudinal axis of
the fluid coupler, or in an orientation substantially perpendicular
to the longitudinal axis of the fluid coupler. In some embodiments,
the at least one sensor includes an exposed electroactive surface
area with a dimension substantially equal to a width of a lumen of
the fluid coupler, such as described with reference to FIGS. 2M-2P.
In some further embodiments, the exposed electroactive surface area
intersects the lumen of the fluid coupler. In preferred
embodiments, the fluid coupler is configured to provide
identification information associated with a flow profile, such as
described with reference to FIG. 10E, herein. For example, in one
embodiment, the system is configured to program the flow profile of
the flow control device in response to automatic receipt of the
identification information. In some embodiments, the identification
information is provided by a mechanical structure of the fluid
coupler. For example, in some embodiments, a portion of the fluid
coupler is configured to form a mechanical interlock with a portion
of the flow control device and/or the tubing assembly, wherein
formation of the mechanical interlock automatically selects a flow
profile associated with the fluid coupler (or with a catheter size,
with a type of host (e.g., infant host versus child host versus
adult host) and the like). In some other embodiments, the fluid
coupler includes electronics that provide identification
information. In still other embodiments, the fluid coupler includes
both a mechanical structure and electronics configured to provide
the identification information associated with the flow profile. In
some embodiments, the fluid coupler includes multiple lumens,
wherein the system is configured and arranged to infuse a fluid a
fluid in a first lumen of the fluid coupler, and to draw back a
biological sample into a second lumen of the fluid coupler. For
examples, in embodiments wherein the at least one analyte sensor is
located in the second lumen, a hydration, nutrition and/or
medicament solution can be infused via the first lumen without
substantially affecting the at least one sensor. In some
embodiments, the system is configured to infuse another solution,
such as a calibration, wash or hydration solution through the
second lumen of the fluid coupler, such as for washing the sensor
and/or for making reference measurements. While some embodiments
include a single analyte sensor located in the fluid coupler, in
other embodiments, the at least one analyte sensor includes at
least 2, 3, 4, 5, 6, 7, 8, or 9 or more analyte sensors. In some
embodiments, two or more of the analyte sensors are configured to
detect the same analyte, such as for a back-up (e.g., in case a
first sensor fails the other sensor can be used) and/or as a
quality check (e.g., to make sure the sensors are working
substantially the same). In other embodiments, the analyte sensors
are each configured to measure a different analyte. In still other
embodiments, some of the analyte sensors are configured to detect
the same analyte, while the remaining analyte sensors are
configured to detect different analytes. One skilled in the art
appreciates the variety of possible analyte sensor configuration
combinations.
[0434] In some embodiments, the system is configured and arranged
such that the at least one analyte sensor is located within about
35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or less from a source
of the biological sample. In some embodiments, the at least one
analyte sensor is located (e.g., within the vascular access
device), such that the analyte sensor is bathed in the sample when
about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 25,
15, 10, or 5-.mu.l or less of the bodily fluid (e.g., blood) is
drawn back. In some embodiments, a lumen of the second portion is
wider than a lumen of the first portion. For example, the lumen of
the fluid coupler is wider than the lumen of the catheter. In some
embodiments, the second portion is a fluid coupler, wherein the
fluid coupler is configured to releasably mate with the catheter.
In some embodiments, the at least one sensor is incorporated into
the second portion. For example, in one embodiment, the at least
one sensor is located on an inner surface (e.g., the lumenal
surface) of the fluid coupler (e.g., the second portion). In a
further embodiment, the at least one sensor is disposed within a
lumen of the fluid coupler (e.g., the second portion). In some
embodiments, at least a portion of the at least one sensor is
disposed in an orientation substantially parallel to a longitudinal
axis of the fluid coupler (e.g., the second portion). In some
embodiments, at least a portion of the at least one sensor is
disposed in an orientation substantially perpendicular to a
longitudinal axis of the fluid coupler (e.g., the second portion).
In some embodiments, the at least one sensor includes an exposed
electroactive surface area with a dimension substantially equal to
a width of a lumen of the fluid coupler (e.g., the second portion).
In some embodiments, the exposed electroactive surface area
intersects the lumen of the fluid coupler (e.g., the second
portion). In some embodiments, the fluid coupler (e.g., the second
portion) is configured to provide identification information
associated with the flow profile. In some embodiments, the system
is configured to program the flow profile of the flow control
device in response to automatic receipt of the identification
information (e.g., via a wired or wireless connection and/or
triggered by a physical and/or operable connection of the vascular
access device (e.g., fluid coupler and/or catheter) with the flow
control device and/or system electronics). In some embodiments, the
identification information is provided by a mechanical structure of
the fluid coupler (e.g., the second portion). In some embodiments,
the identification information is provided by electronics of the
fluid coupler (e.g., the second portion).
[0435] In some embodiments, the at least one analyte sensor is
configured to measure an analyte selected from the group consisting
of albumin, alkaline phosphatase, alanine transaminase, aspartate
aminotransferase, bilirubin, blood urea nitrogen, calcium,
CO.sub.2, chloride, creatinine, glucose, gamma-glutamyl
transpeptidase, hematocrit, lactate, lactate dehydrogenase,
magnesium, oxygen, pH, phosphorus, potassium, sodium, total
protein, uric acid, a metabolic marker and a drug. In some
embodiments, the at least one analyte sensor includes at least
three analyte sensors located within the second portion of the
vascular access device and configured to measure at least three
analytes. For example, in one embodiment the second portion of the
vascular access device is the second portion of a catheter (e.g.,
the ex vivo portion, the hub), and the at least three analyte
sensors are located therein. In some embodiments, the at least one
analyte sensor includes at least eight analyte sensors located
within the second portion of the vascular access device (e.g., the
fluid coupler or the second portion (e.g., hub or ex vivo portion)
of a catheter) and configured to measure at least eight
analytes.
[0436] In one exemplary embodiment, the catheter is a peripheral
catheter (e.g., for insertion into a vein located in an arm and/or
leg) having the analyte sensor located within the catheter hub. In
some embodiments, the volume that the catheter hub can hold has
been restricted (e.g., reduced), such as by fabricating the
catheter hub with a reduced internal diameter. In this embodiment,
the sample is drawn back only about 50, 45, 40 or 35-mm (e.g., into
the catheter hub, depending upon the length of the catheter), such
that the analyte sensor is bathed in the sample.
[0437] In yet another exemplary embodiment, the analyte sensor is
located within the lumen of a fluid coupler (e.g., configured for
fluid connection with a catheter). In this embodiment, when the
fluid coupler is coupled to an implanted peripheral catheter, the
sensor's electrodes are bathed in a sample when the sample is drawn
back a distance of about 50, 45, 40, 35 or 30-mm, depending upon
the length of the catheter, which correlates with a sample volume
of about 500, 450, 400, 350, 300 or 250-.mu.1 or less.
[0438] Alternatively, when the catheter is coupled to a central
catheter (e.g., a catheter for insertion into vessels in the body,
such as to access the heart), the distance the sample is drawn back
(e.g., to sufficiently contact/bathe the electrodes such that
analyte measurements can be taken) is much farther (e.g., relative
to the distance of draw-back into a peripheral catheter), since
central catheters range from about 12 to about 24-inches in length.
Thus, in this exemplary embodiment, the distance the sample is
drawn back includes the entire length of the central catheter
(including the catheter's hub) and a portion of the connector, such
as but not limited to about 12, 13, 14 or 15 inches, to about 18,
19, 20, 21, 22, 23, 24 or 25-inches or more, depending upon the
length of the catheter, which can correspond with a sample volume
of about 1.5-ml, 1.25-ml, 1-ml, 900-.mu.l, 800-.mu.l, 700-.mu.l,
600-.mu.l or 500-.mu.l or less, depending upon the catheter's size
and/or configuration, the fluid coupler's configuration, and the
like. If the sensor extends from the fluid coupler into the central
catheter, the distance the sample is drawn back is reduced to a
portion of the central catheter's length, with a corresponding
reduction in sample volume.
[0439] FIG. 2H is a cross section of a vascular access device
including a plurality of analyte sensor 240 in another embodiment.
In this embodiment, the vascular access device is a connector 250
(e.g., fluid coupler) and/or valve, such as but not limited to a
Leur lock, a Y-connector, a T-connector, and an X-connector. In
general, the connector 250 (e.g., fluid coupler) is configured to
be coupled/connected to vascular access devices, such that a fluid
can pass between two vascular access devices coupled to the
connector's two ends. For example, a first end of the connector can
be coupled to a catheter or cannula implanted (e.g., pre-implanted)
in a host's vein or artery, and a second end of the connector can
be coupled to another connector, a valve, IV tubing, and IV bag, a
test device, etc. In some embodiments, the connector 240 is a fluid
coupler, such as described with reference for FIGS. 1A-1M and
2M-2S. The connector includes a duct 254 (e.g., lumen) and a
proximal orifice 258. A plurality of analyte sensors 240 is
disposed within the duct 254. As described with reference to the
device shown in FIG. 2G, the plurality of analyte sensors can be
disposed within the duct 254 using any means known in the art. In
some embodiments, one or more of the analyte sensors are deposited
(e.g., formed) on a surface of the duct 254 (e.g., on an interior
surface). In some embodiments, one or more of the analyte sensors
are applied to the surface of the duct 254. In some embodiments,
one or more of the analyte sensors is configured to pass through
(e.g., intersect) the wall 252 of the connector such that a first
portion of the sensor 240 is disposed within the duct 254 and a
second portion of the sensor 240 is disposed at the exterior of the
connector 250 (described in more detail herein).
[0440] FIG. 2I is a cross-section of a vascular access device of
either FIG. 2G or FIG. 2H taken along line 2I-2I, looking towards
the proximal end of the vascular access device. The device includes
a duct/lumen 212b/254 defined by a wall 260. The in vivo orifice
(also referred to as the proximal orifice with relation to the
host) of the device is represented by circle 212b/258. As shown in
this embodiment, a plurality of sensors can be disposed within the
duct, such as but not limited at the in the interior surface of the
wall. In some embodiments, the device includes two analyte sensors.
In some embodiments, the device includes 3, 4, 5, 6, 7 or more
analyte sensors. In some embodiments, one or more of the analyte
sensors are configured to be disposed entirely within the duct
(e.g., to not protrude out of the duct). In some embodiments, one
or more analyte sensors can be configured such that a portion
thereof protrudes out the duct, such as but not limited to into the
lumen of a catheter 212 or through the proximal orifice 212b/258 of
the device. In some embodiments, a portion or one or more of the
sensors can be configured to protrude through the ex vivo orifice
(also referred to as the distal orifice with ration to the host) of
the device. The analyte sensors 240 disposed within the device can
be of any configuration and can use any detection method, including
but not limited to electrochemical, enzymatic, optical,
radiometric, chemical, physical, immunochemical and the like,
including a combination thereof.
[0441] FIG. 2J is a cross-section of a vascular access device of
either FIG. 2G or FIG. 2H taken along line 2I-2I, looking towards
the proximal end of the vascular access device, prior to
installation of any analyte sensors 240. FIG. 2K depicts the FIG.
2J device after sensor installation. In this embodiment, a
plurality of sensor sites 262 is located at the surface of the wall
260. While FIGS. 2J and 2K depict the sensor sites 262 as being
depressions in the wall 260, the sensor sites 262 can be of any
configuration, such as but not limited to a portion of the wall's
inner surface that is flush with the remaining portion of the inner
surface, a textured portion of the inner surface, a channel, a
hole, and the like. In some embodiments, the sensor sites can have
a plurality of configurations. For example, in a device including
four sensor sited 262, a first site can have a first configuration,
the second and third sites a second configuration, and the fourth
site yet another configuration.
[0442] FIG. 2L is a cross-section of a vascular access device of
either FIG. 2G or FIG. 2H taken along line 2I-2I, looking towards
the proximal end of the vascular access device, in an alternative
embodiment. In this embodiment, the sensor sites 262 can be formed
to include a plug 264 and/or a breakaway portion of the wall 260,
which can be removed to enable sensor installation. For example, a
plug/breakaway portion can be pushed and/or punched out of the
sensor site and then the sensor installed in the sensor site. In
some embodiments, removal of a plug/breakaway portion creates a
channel through the wall, such that a sensor (at least a portion
thereof) can be inserted through the channel and into the duct 254.
In some embodiments, the portion of an installed sensor remaining
on the external side of the wall is configured to functionally
connect to sensor electronics, as is appreciated by one skilled in
the art. While not wishing to be bound by theory, it is believed
that this configuration enables increased accuracy and speed in
device assembly because the sensors can be manufactured separately
from the device and then installed into the device in a
"plug-and-play" fashion.
[0443] FIG. 2M illustrates another embodiment of the analyte sensor
system configured to measure one or more analytes in a bodily fluid
of a host, namely a fluid coupler (e.g., connector) 250 having a
wall 260, a lumen 254, a first end 258 configured and arranged for
fluid communication with a vascular access device, and a second end
256 configured and arranged for fluid communication with an
infusion device, such as via IV tubing and/or a tubing assembly,
such as described elsewhere herein. The analyte sensor 240 (e.g.,
240a, 240b and/or 240c) is configured and arranged to generate a
signal associated with an analyte in a sample of a circulatory
system of a host (e.g., a bodily fluid such as but not limited to
blood), wherein at least a portion of the analyte sensor is
disposed within the lumen 254 of the fluid coupler 250.
[0444] In preferred embodiments, the device is configured such
that, when it is fluidly connected to an implanted catheter, at
least a portion of the analyte sensor 240 is located within about
60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1-mm or
less from the source of the sample, such as from the tip of the
inserted catheter. In some embodiments, the analyte sensor is
located within about 30-mm or less from a source of the sample.
Advantageously, locating the sensor close to the source of sample
(e.g., bodily fluid, blood) and configuring the system for use of
very small samples, including return of the sample to the host,
limits the loss of blood from the host, thereby enabling the use of
the device in circumstances, such as neonatal and critical care
settings, wherein loss of blood is a critical issue for host health
and/or survival. For example, in one embodiment, the device is
configured such that analyte sensor is bathed in the sample when
about 1000, 900, 800, 700, 600, 500, 400, 300, 200, 100, 50, 25,
15, 10, or 5-.mu.l of the bodily fluid is drawn back.
[0445] In some embodiments, the vascular access device (e.g., a
catheter or a fluid coupler) includes a longitudinal axis. For
example, if the device is a catheter, the longitudinal axis can
extend from the tip 212b of the in vivo portion to the hub orifice
218c. In another example, if the device is a fluid coupler, the
longitudinal axis can extend from the proximal orifice 258 to the
distal orifice 256. The analyte sensor (e.g., the electrodes,
electroactive surfaces) can be disposed in the catheter hub or
fluid coupler lumen in various orientations with relation to the
longitudinal axis. For example, in some embodiments, the analyte
sensor is disposed in an orientation parallel to the longitudinal
axis. For example, in one embodiment, the analyte sensor intersects
the wall 260, such that the electroactive surface(s) are located
along an interior (e.g., luminal) surface of the wall. For example,
the electrode can intersect the wall at two points that are
separated by a longitudinal distance on the wall, such that the
electroactive surface(s) are oriented parallel to the longitudinal
axis of the device. For example, with reference to the device of
FIG. 2M, in an alternative embodiment, one or more of the
electrodes (e.g., 240a, 240b and/or 240c) can intersect the wall at
two points along one side of the device (e.g., 260a or 260b) such
that the length of the electrode runs parallel to the longitudinal
axis of the device. For example, if the device includes three
electrodes, the electrodes can be spaced about the inner
circumference of the lumen, such as but not limited to equidistant
from each other, wherein each electrode runs parallel along the
luminal wall in an orientation parallel to the longitudinal axis of
the device. In another embodiment, one or more sensors (e.g.,
twisted and/or bundled working and/or reference electrodes, instead
of individual electrodes) can be placed in the device such that a
length of the electroactive surfaces of the sensor(s) is parallel
to the longitudinal axis of the device. For example, the device
could include 2, 3, 4, 5 or more analyte sensors. In some
embodiments, the reference electrode is disposed remotely from the
working and/or counter electrode(s). In some embodiments, one
reference electrode is configured to function as the reference
electrode for two or more analyte sensors.
[0446] In some embodiments, the electrode(s) are disposed within
the catheter hub or fluid coupler such that they are oriented
perpendicularly to a longitudinal axis of the device. Returning
again to the exemplary embodiment illustrated in FIG. 2M, the
device can be configured such that the individual electrodes (e.g.,
240a, 240b and 240c) intersect wall 260 on opposite sides (e.g.,
260a and 260b) of the device, such that each electrode is
perpendicular to the longitudinal axis of the fluid coupler. For
example, in some embodiments, the first and second points can be
connected by a line that is perpendicular to the longitudinal axis
of the device. One skilled in the art appreciates that while FIG.
2M illustrates individual electrodes 240a, 240b and 240c, in other
embodiments, one complete sensor (e.g., having bundled and/or
twisted working, counter and/or reference electrodes) can be used.
In some further embodiments, the device is configured such that the
electroactive surface of each electrode has a surface area having a
first dimension (e.g., length or width) substantially equal to a
diameter of the lumen of the connector or hub. For example, in the
embodiment shown in FIG. 2M, the length of the electroactive
surfaces (e.g. window 343 of FIG. 3B) can be substantially equal to
the inner diameter of the fluid coupler. In a further example, each
electrode can be formed, including the membrane, as described
herein, inserted through the wall(s) of fluid coupler (e.g.,
through holes or using a needle to pierce the wall(s) formed of
elastomeric material as described herein), such that the
electroactive surface is disposed within the lumen, excess
electrode material removed from one side (e.g., 260b) and then
electrical connection with system electronics (e.g., via soldering
electrical wires) on the opposite side (e.g., 260a).
[0447] While the electrodes of the embodiment illustrated in FIG.
2M are disposed individually, additional configurations are
contemplated in the preferred embodiments. For example, in some
embodiments, the electrodes are bundled and/or twisted, such that
the electrodes intersect the wall together. In other embodiments,
the analyte sensor includes an electrode located within the lumen
of the in vivo portion of the catheter, such as at the tip 212b of
the catheter. In another embodiment, the electrode is located at
and/or on the luminal surface of the in vivo portion of the
catheter. For example, in some embodiments, the electrodes are
deposited on a flexible support, which is inserted into the lumen.
In another example, in some embodiments, the electrodes are
deposited on the flexible support when the flexible support having
a planar configuration, which is then cut to size, rolled into a
cylindrical configuration (such that the electrodes are within the
interior of the cylinder), and then inserted into the catheter
lumen. In a further exemplary embodiment, the flexible support is
formed of an appropriate material to form the in vivo portion of a
catheter, electrodes are applied to a surface of the material
(e.g., when in a planar configuration) using methods known in the
art, the material is cut to size, rolled and the cut edges sealed
(e.g., by welding or an adhesive), and a catheter hub applied
thereto, such that the rolled and sealed flexible support forms the
wall of the in vivo portion of the catheter, wherein the electrodes
are located on the luminal surface of the electrode wall. Forming
the catheter and electrodes in this manner enables easy
manufacturing techniques and a variety of electrode configurations,
such as but not limited to linear electrodes, circular electrodes,
electrodes that spiral along/around the interior of the catheter,
and the like. In additional embodiments, a plurality of analyte
sensors (e.g., including two or more electrodes) can be disposed in
the catheter lumen, such that two or more analytes can be measured,
or such that redundant sensors (e.g., two or more glucose sensors)
can measure a single analyte.
[0448] FIG. 2N illustrates an embodiment of a fluid coupler
configured to include two or more analyte sensors, namely the fluid
coupler is divided into two or more channels, each of which
includes an analyte sensor. In one illustrated embodiment, the
fluid coupler is divided into two flow channels 254 (e.g., two
lumens), each with an analyte sensor disposed therein (e.g.,
electrode 240a, 240b and 240c). For example, the analyte sensor in
one flow channel can be configured to detect glucose and the
analyte sensor in the other flow channel can be configured to
detect a cardiac marker, in one embodiment. In another illustrated
embodiment, the fluid coupler is divided into three flow channels
(e.g., three lumens), each with an analyte sensor disposed therein.
Inclusion of additional lumens enables incorporation of additional
analyte sensors such that each analyte sensor receives a sample
uncontaminated by reagents and/or products and/or for infusion of a
medicament. For example, a glucose sensor using GOX to detect
glucose generates H.sub.2O.sub.2, which can affect the other
sensors of the device. If the sensors are located in separate
lumens, the H.sub.2O.sub.2 generated by the glucose sensor cannot
affect the sensors located in the other lumens. As a further
example, sample that is drawn back flows into each of the lumens,
such that each of the sensors is bathed in sample uncontaminated by
reagents and reaction products from another of the sensors. When
the device is flushed (e.g., with saline or calibrant solution),
each of the sensors are washed and does not contaminate another
sensor with its reagents/reaction products. Accordingly, in some
embodiments, the fluid coupler is divided into additional channels,
such as a network of 4, 5, 6, 7, 8, 9, 10 or more channels, such
that panels of analytes can be continuously measured at the same
time. In some embodiments, the fluid coupler is miniaturized,
thereby providing a micro-scale, multi-sensor device, such that
about 5, 10, 15, 20, 25, 30, 40, 50, 100 or more analytes can be
continuously monitored simultaneously. This configuration provides
certain advantages, such as but not limited to, this device is
amenable to high-throughput, modular manufacturing on an assembly
line; the device can be connected to a wide variety of catheters
currently in use; a plurality of sensors can be used
simultaneously; and the device is amenable to custom-made analyte
panels (e.g., Hospital #1 wants glucose and oxygen sensors, while
Hospital #2 wants glucose, creatinine and temperature sensors).
[0449] A variety of techniques can be used to manufacture an
integrated fluid coupler and analyte sensor device. For example, in
some embodiments, the wall 260 is formed of a self-sealing material
(not shown), such that the analyte sensor can be inserted through
the wall using a needle. For example, a needle containing the
sensor in its barrel can be inserted through the wall, followed by
withdrawal of the needle over the sensor, such that the sensor
remains inserted through the wall. For example, polymer tubing,
such as but not limited to silicone tubing, can be used to form the
central body of a fluid coupler, and connector ends (e.g.,
configured for connecting the fluid coupler to a catheter and/or
tubing) attached thereto. Additional methods of manufacturing the
preferred embodiments are detailed in the section entitled
"Multi-Sensor Apparatus."
[0450] FIGS. 2O and 2P illustrate another method of manufacturing
an integrated fluid coupler and analyte sensor device, such as that
shown in FIG. 2M. In one embodiment, the fluid coupler is formed of
two or more mateable portions (e.g., 260-1, 260-2), wherein the
first and second mateable portions are configured and arranged to
form a seal 260e when mated together, such that the lumen is formed
254. For example, the two mateable portions can be formed by
injection molding a suitable medical-grade plastic. In the
embodiment shown in FIG. 2O, the two mateable portions 260-1, 260-2
are configured to mate together, such as but not limited to in a
clam shell configuration. One or both of the two mateable portions
260-1, 260-2 includes an indentation 260c on the sealing edge(s)
(e.g., mating edges) configured to receive an analyte sensor
(and/or an electrode). In the illustrated embodiment, the two
mateable portions each include three indentations, wherein the
indentations are configured to receive the electrodes 240. In some
embodiments, the sensor electrodes are inserted separately (e.g.,
as opposed to in a bundled or twisted configuration). In a further
embodiment, the electrodes can be spaced along the length of the
lumen to optimize fluid flow and analyte detection. For example, in
some embodiments, the electrodes are spaced equally within the
lumen (e.g., the distance between electrodes 240a and 240b is
substantially equal to the distance between electrodes 240b and
240c). In some embodiments, the device is configured such that the
diameter of the lumen is substantially the same as the length of
the electroactive surfaces (e.g., which span the lumen). Additional
configurations are contemplated, such as non-linear spacing and
non-equal spacing of the electrodes.
[0451] Referring again to FIGS. 2O and 2P, in some embodiments, a
grommet 260d can be included at the point at which the electrode
intersects the mated wall. In other embodiments, the wall
surrounding the electrode (e.g., at 260d) can be welded, to form a
seal between the electrode and the wall. In some embodiments, the
seal is fluid-tight. In some embodiments, a portion of the wall
material is melted by the welding, such that a portion of the
melted wall material can soak into the membrane of the electrode.
FIG. 2P illustrates an alternative method of forming the integrated
fluid coupler and analyte sensor device, wherein the two mateable
portions 260-1, 260-2 comprise cylinders configured to mate
together such that the analyte sensor 240 spans the lumen 254.
[0452] A connection between the analyte sensor (and/or individual
electrodes) and sensor electronics can be made on the exterior
surface of the fluid connector. For example, in some embodiments,
the analyte sensor electrodes are soldered to wires, which in turn
make electrical connection with the sensor electronics. In other
embodiments, the electrodes are clipped off substantially flush
with the exterior surface of the wall and a PCB 20t (e.g.,
configured to make suitable electrical connection with each of the
electrodes) is attached to the clipped-off ends of the electrodes
(e.g., via adhesive or welding), such that the electrical
connections are made; the PCB is then used to connect the sensor to
sensor electronics. In still other embodiments, elastomeric
contacts can be used to make a connection between the electrodes
and sensor electronics, in a manner similar to that illustrated in
FIGS. 1H and 1J. Additional methods of connecting analyte sensors
to sensor electronics are appreciated by those skilled in the
art.
[0453] FIG. 2Q illustrates an alternative embodiment of an
integrated fluid coupler and analyte sensor device, in which the
electrodes are formed of conductive elastomeric material (e.g.,
contacts 240). A portion of the fluid coupler can be configured
with one or more holes 260c to receive the elastomeric contacts.
For example, the fluid coupler can be injection molded of plastic,
including the holes 260c configured to receive the elastomeric
contacts 240. The electrode/elastomeric contacts can be formed of
any conductive elastomeric materials, such as but not limited to
carbon black elastomer. Each elastomeric contact is configured with
an interior side 240e and an exterior side 240d. The interior side
is configured and arranged as an electrode, such as one or more
working electrodes (plus and/or minus enzyme), a counter electrode
or a reference electrode, as described elsewhere herein. The
exterior side is configured and arranged for electrical connection
with the sensor electronics. The electrode/elastomeric contact can
have any useful shape, such that the interior side can be inserted
through a hole of the fluid coupler, such that the electroactive
surface can be bathed by a sample drawn back into the fluid
coupler, and such that the exterior side is sufficiently exposed
for making the electrical connection with the sensor electronics.
The conductive material can be formed into any shape. For example,
the electrode/elastomeric contact can be a ball, or wedge or
cylinder. In the embodiment shown in FIG. 2Q, the
electrode/elastomeric contact includes a cylindrical body with a
flat electroactive surface at the interior side 240e, and sloped or
flared sides. The interior side 240e is configured and arranged to
be substantially flush with the lumenal surface of the fluid
conduit wall, such that fluid turbulence, biofouling and/or
clotting is/are substantially reduced when the device is in use.
The exterior side 240d includes a flat butt end, which is somewhat
larger in diameter than cylindrical body, and a shoulder. In some
embodiments, the elastomeric material is sufficiently pliable that
the elastomeric contact can conform to the structure of the hole,
when it is inserted into the hole; such that it makes a
substantially water-tight seal with the wall of the fluid coupler.
For example, in the illustrated embodiments, the flared sides are
configured to conform to the hole (e.g., an interference fit), such
that the conformed side and the shoulder make a water-tight seal
with the wall of the fluid conduit.
[0454] Electrical connection between the electrode/elastomeric
contacts 240 and sensor electronics can be made with their exterior
surfaces by any method known in the art. For example, in some
embodiments, a PCB 20t configured and arranged for electrical
contact with the elastomeric contacts is adhered over the
elastomeric contacts. A cover, such as one configured with a female
connector 20n (e.g., see cover 20k in FIGS. 1H-1J) is adhered over
the PCB, or the PCB is hard-wired to an electrical cable. In
another embodiment, the electrode/elastomeric contacts are simply
soldered to the wires of an electrical cable. In still other
embodiments, conductive traces (e.g., vias) is applied to the
exterior surface of the fluid conduit (e.g., prior to insertion of
the electrode/elastomeric contacts) such that when the elastomeric
contacts are inserted into the holes, the shoulder of each
electrode/elastomeric contact makes an electrical connection with
one of the conductive traces. The electrical traces, in turn, make
electrical connections with sensor electronics, as is known to one
skilled in the art.
[0455] Use of electrode/elastomeric contacts 240 enables unique
manufacturing methods which are amenable to high through-put,
modular manufacturing. In one embodiment, the individual
electrode/elastomeric contacts are formed and then processed in
batches, such as to deposit the electroactive surfaces and
membranes on the interior surfaces. For example, to prepare a batch
of working electrode/elastomeric contacts, a batch of unprepared
elastomeric contacts (e.g., 100, 1000, etc.) can be placed,
head-up, in a holder. Platinum or other conductive electrode
material can then be deposited on the heads, sides and/or entire
electrode/elastomeric contacts using suitable means such as
electroplating, electrospinning, spraying, and the like, to form
the electroactive surfaces. A membrane is applied as one or more
layers, using known thin-film or thick-film techniques. To form
reference electrode/elastomeric contacts, Ag/AgCl particles or
other conductive electrode material can be mixed or otherwise
formed in or on the material used to form the electrode/elastomeric
contacts, or Ag/AgCl can be applied to the interior surfaces of the
reference electrode/elastomeric contacts, for example.
[0456] In a another embodiment, the electrode/elastomeric contacts
are formed by preparing a sheet of the elastomeric conductive
material, preparing a surface of the sheet, such as forming an
electroactive surface thereon, and then punching the individual
electrode/elastomeric contacts from the sheet.
[0457] FIG. 2R is a cross-section of another embodiment of a fluid
coupler including a continuous analyte sensor 240 disposed within
the lumen 254. Namely, a central body 270 is inserted within the
lumen. The central body includes conductive bodies 272 disposed
within a non-conductive material. Each conductive body 272 includes
a conductive member 273, for making electrical contact with sensor
electronics. The sensor electrodes 240 are deposited on the
conductive bodies 272, such that when the central body 270 is
inserted into the lumen of the fluid coupler, the electrodes are
bathed in sample when the sample is drawn back. In some
embodiments, the conductive members provide stabilization to the
central body. In other embodiments, the central body and conductive
members are configured and arranged such that the lumen is divided
into a plurality of chambers (e.g., smaller lumens), such that a
plurality of analyte sensors are deposited on the conductive bodies
and such that each analyte sensor contacts a separate sample (e.g.,
uncontaminated by reagents or reaction products from an analyte
sensor in another chamber). In one embodiment, the central body is
configured as an elongated core, such as but not limited to a
cylindrical core. In some embodiments, the central body 270 is
configured as a plurality of conductive bodies 272, which run the
length of the central body, bundled in a dielectric material,
wherein the conductive members 273 extend out an end of the central
body (e.g., rather than out the sides as shown in FIG. 2R). In this
embodiment, a plurality of analyte sensors can be deposited on the
conductive bodies, wherein the central body is inserted into the
lumen of the fluid coupler.
[0458] FIG. 2S illustrates yet another embodiment of an analyte
sensor disposed in a fluid coupler, including an electrode support
280 having one or more analyte sensors 240 deposited thereon. The
electrode support 280 is configured and arranged to optimize fluid
flow there around and to substantially reduce biofouling and/or
clotting thereon. For example, in some embodiments, the electrode
support 280 is cigar or football shaped. The electrodes can be
working, counter and/or reference electrodes. In some embodiments,
the electrode support 280 is stabilized by stabilizers 282. While
the stabilizers 282 shown in FIG. 2S are "fin" shaped, a variety of
other shapes, such as projections, extensions, detents, and the
like can be used. In preferred embodiments, the stabilizers
substantially maintain the electrode support 280 within the fluid
stream such that the electrode support 280 is substantially
immobile, such that the flow of fluid about the electrode support
280 is substantially even (e.g., the same rate there around).
[0459] In some embodiments, the device is formed by injection
molding, using techniques known in the art. In one exemplary
embodiment, the sensors are placed in a mold, which is configured
to hold the sensors in such an orientation that after the injection
molding procedure, the sensors will be in the correct location
and/or orientation for correct function of the device. After the
sensors are placed in the mold, the mold is closed and injected
with a material (e.g., molten plastic). During the injection
molding process, the wall 260 of the device is thus formed about a
portion of each sensor 240, such that a sensing portion of each
sensor (e.g., electroactive surface) will be disposed within the
duct 212b/258 and another portion of each sensor (e.g., a portion
configured for connection to sensor electronics) will be disposed
at the exterior of the device. Similar manufacturing techniques are
used for the manufacture of syringes and lancets, wherein the
plastic portion of the device is formed about a portion of the
needle.
[0460] In a medical setting, a variety of vascular access devices
can be simultaneously made available for use in conjunction with a
flow control device, as described elsewhere herein. As is
understood by one skilled in the art, each vascular access device
can require a unique flow profile, such that the flow control
device infuses and draws back the correct amounts of fluid and/or
sample, at the correct time and for the correct lengths of time, to
enable optimal sensor operation. In some circumstances, a caretaker
may select the wrong flow profile for an installed vascular access
device; a medical error that might harm the patient. Accordingly,
in some embodiments, the vascular access device is configured and
arranged to provide identification information to flow control
device, wherein the identification information is associated with
the flow profile. For example, in some embodiments the
identification information is provided by a mechanical structure
(e.g., an engageable mechanical interlock wherein the vascular
access device includes one of two portions of the mechanical
interlock and the flow control device includes the second of the
two portions of the mechanical interlock). In some embodiments, the
identification information is provided by electronics of the
vascular access device (e.g., a bar code (e.g., identified by a bar
code scanner incorporated into the flow control device), an RFID
chip configured for communication with the electronics of the
vascular access device and the like). In some preferred
embodiments, a flow profile associated with the vascular access
device is initiated by the flow control device, after
identification of the vascular access device via the identification
module. In preferred embodiments, the system is configured to
program the flow profile of the flow control device in response to
automatic receipt of the identification information (e.g.,
transmission of the identification information without required
user interaction). In this embodiment, because the user does not
enter which flow profile to use with the vascular access device,
user error is reduced, which in turn increases patient safety.
[0461] While not wishing to be bound by theory, a number of the
systems and methods disclosed in the preferred embodiments (e.g.,
an analyte sensor to be disposed in communication with the host's
blood), can be employed in transcutaneous (e.g., transdermal) or
wholly implantable analyte sensor devices. For example, the sensor
could be integrally formed on the in vivo portion of a subcutaneous
device or a wholly implantable device. As another example, an
enlarged surface area (e.g., bulbous end) can useful in the design
of a transcutaneous analyte sensor.
[0462] Exemplary Sensor Configurations
[0463] Referring to FIGS. 3A to 3C, in some embodiments, the sensor
can be configured similarly to the continuous analyte sensors
disclosed in co-pending U.S. Patent Publication No.
US-2007-0197889-A1 herein incorporated by reference in its
entirety. The sensor includes a distal portion 342, also referred
to as the in vivo portion, adapted for insertion into the catheter
as described above, and a proximal portion 340, also referred to as
an ex vivo portion, adapted to operably connect to the sensor
electronics. Preferably, the sensor includes two or more
electrodes: a working electrode 344 and at least one additional
electrode, which can function as a counter electrode and/or
reference electrode, hereinafter referred to as the reference
electrode 346. A membrane system is preferably deposited over the
electrodes, such as described in more detail with reference to
FIGS. 3A to 3C, below.
[0464] FIG. 3B is an expanded cutaway view of a distal portion of
the sensor in one embodiment, showing working and reference
electrodes. In preferred embodiments, the sensor is formed from a
working electrode 344 (e.g., a wire) and a reference electrode 346
helically wound around the working electrode 344. An insulator 345
is disposed between the working and reference electrodes to provide
electrical insulation therebetween. Certain portions of the
electrodes are exposed to enable electrochemical reaction thereon,
for example, a window 343 can be formed in the insulator to expose
a portion of the working electrode 344 for electrochemical
reaction.
[0465] In preferred embodiments, each electrode is formed from a
fine wire with a diameter of from about 0.001 inches or less to
about 0.050 inches or more, for example, and is formed from, e.g.,
a plated insulator, a plated wire, or bulk electrically conductive
material. For example, in some embodiments, the wire used to form a
working electrode is about 0.002, 0.003, 0.004, 0.005, 0.006,
0.007, 0.008, 0.009, 0.010, 0.015, 0.020, 0.025, 0.030, 0.035,
0.040 or 0.045 inches in diameter. Although the illustrated
electrode configuration and associated text describe one preferred
method for forming a sensor, a variety of known sensor
configurations can be employed with the analyte sensor system of
the preferred embodiments, such as U.S. Pat. Nos. 5,711,861,
6,642,015, 6,654,625, 6,565,509, 6,514,718, 6,465,066, 6,214,185,
5,310,469, 5,683,562, 6,579,690, 6,484,046, 6,512,939, 6,424,847,
and 6,424,847, for example. Each of the above patents is
incorporated in its entirety herein by reference. The above patents
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. It is noted that
much of the description of the preferred embodiments, for example
the membrane system described below, can be implemented not only
with in vivo sensors, but also with in vitro sensors, such as blood
glucose meters (SMBG).
[0466] In some embodiments, the working electrode comprises a wire
formed from a conductive material, such as platinum,
platinum-iridium, palladium, graphite, gold, carbon, conductive
polymer, alloys, and 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.
[0467] In some embodiments, the working electrode is formed of
platinum-iridium or iridium wire. In general, platinum-iridium and
iridium materials are generally stronger (e.g., more resilient and
less likely to fail due to stress or strain fracture or fatigue).
It is believed that platinum-iridium and/or iridium materials can
facilitate a wire with a smaller diameter to further decrease the
maximum diameter (size) of the sensor (e.g., in vivo portion).
Advantageously, a smaller sensor diameter both reduces the risk of
clot or thrombus formation (or other foreign body response) and
allows the use of smaller catheters.
[0468] The electroactive window 343 of the working electrode 344 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 reacts with the
surface of the working electrode producing two protons (2H.sup.+),
two electrons (2e.sup.-) and one molecule of oxygen (O.sub.2),
which produces the electronic current being detected.
[0469] In preferred embodiments, the working electrode 344 is
covered with an insulating material 345, 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 working electrode.
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). While not wishing
to be bound by theory, it is believed that the lubricious (e.g.,
smooth) coating (e.g., parylene) on the sensors of some embodiments
contributes to minimal trauma and extended sensor life. While
parylene coatings are generally preferred in some embodiments, any
suitable insulating material can be used, for example, fluorinated
polymers, polyethyleneterephthalate, polyurethane, polyimide, other
nonconducting polymers, and 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. In some alternative
embodiments, however, the working electrode may not require a
coating of insulator.
[0470] The reference electrode 346, which can function as a
reference electrode alone, or as a dual reference and counter
electrode, is formed from silver, silver/silver chloride, and the
like. In some embodiments, the reference electrode 346 is
juxtapositioned and/or twisted with or around the working electrode
344; however other configurations are also possible (e.g., coiled
within the fluid connector/hub 18 or within a fluid coupler 20 or
an intradermal or on-skin reference electrode). In the illustrated
embodiments, the reference electrode 346 is helically wound around
the working electrode 344. The assembly of wires is then optionally
coated or adhered together with an insulating material, similar to
that described above, so as to provide an insulating
attachment.
[0471] In some embodiments, a silver wire is formed onto the sensor
as described above, and subsequently chloridized to form
silver/silver chloride reference electrode. Advantageously,
chloridizing the silver wire as described herein enables the
manufacture of a reference electrode with optimal in vivo
performance. Namely, by controlling the quantity and amount of
chloridization of the silver to form silver/silver chloride,
improved break-in time, stability of the reference electrode and
extended life has been shown with some embodiments. Additionally,
use of silver chloride as described above allows for relatively
inexpensive and simple manufacture of the reference electrode.
[0472] In embodiments wherein an outer insulator is disposed, a
portion of the coated assembly structure can be stripped or
otherwise removed, for example, by hand, excimer lasing, chemical
etching, laser ablation, grit-blasting (e.g., with sodium
bicarbonate or other suitable grit), and the like, to expose the
electroactive surfaces. Alternatively, a portion of the electrode
can be masked prior to depositing the insulator in order to
maintain an exposed electroactive surface area. In one exemplary
embodiment, grit blasting is implemented to expose the
electroactive surfaces, preferably utilizing a grit material that
is sufficiently hard to ablate the polymer material, while being
sufficiently soft so as to minimize or avoid damage to the
underlying metal electrode (e.g., a platinum electrode). Although a
variety of "grit" materials can be used (e.g., sand, talc, walnut
shell, ground plastic, sea salt, and the like), in some preferred
embodiments, sodium bicarbonate is an advantageous grit-material
because it is sufficiently hard to ablate, e.g., a parylene
coating, without damaging, e.g., an underlying platinum conductor.
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.
[0473] In the embodiment illustrated in FIG. 3B, a radial window
343 is formed through the insulating material 345 to expose a
circumferential electroactive surface of the working electrode.
Additionally, sections of electroactive surface of the reference
electrode are exposed. For example, the sections of electroactive
surface can be masked during deposition of an outer insulating
layer or etched after deposition of an outer insulating layer.
[0474] In some applications, cellular attack or migration of cells
to the sensor can cause reduced sensitivity and/or function of the
device, particularly after the first day of implantation. However,
when the exposed electroactive surface is distributed
circumferentially about the sensor (e.g., as in a radial window),
the available surface area for reaction can be sufficiently
distributed so as to minimize the effect of local cellular invasion
of the sensor on the sensor signal. Alternatively, a tangential
exposed electroactive window can be formed, for example, by
stripping only one side of the coated assembly structure. In other
alternative embodiments, the window can be provided at the tip of
the coated assembly structure such that the electroactive surfaces
are exposed at the tip of the sensor. Other methods and
configurations for exposing electroactive surfaces can also be
employed.
[0475] In some embodiments, the working electrode has a diameter of
from about 0.001 inches or less to about 0.010 inches or more,
preferably from about 0.002 inches to about 0.008 inches, and more
preferably from about 0.004 inches to about 0.005 inches. The
length of the window can be from about 0.1 mm (about 0.004 inches)
or less to about 2 mm (about 0.078 inches) or more, and preferably
from about 0.25 mm (about 0.01 inches) to about 0.375 mm (about
0.015 inches). In such embodiments, the exposed surface area of the
working electrode is preferably from about 0.000013 in.sup.2
(0.0000839 cm.sup.2) or less to about 0.0025 in.sup.2 (0.016129
cm.sup.2) or more (assuming a diameter of from about 0.001 inches
to about 0.010 inches and a length of from about 0.004 inches to
about 0.078 inches). The preferred exposed surface area of the
working electrode is selected to produce an analyte signal with a
current in the picoAmp range, such as is described in more detail
elsewhere herein. However, a current in the picoAmp range can be
dependent upon a variety of factors, for example the electronic
circuitry design (e.g., sample rate, current draw, A/D converter
bit resolution, etc.), the membrane system (e.g., permeability of
the analyte through the membrane system), and the exposed surface
area of the working electrode. Accordingly, the exposed
electroactive working electrode surface area can be selected to
have a value greater than or less than the above-described ranges
taking into consideration alterations in the membrane system and/or
electronic circuitry. In preferred embodiments of a glucose sensor,
it can be advantageous to minimize the surface area of the working
electrode while maximizing the diffusivity of glucose in order to
optimize the signal-to-noise ratio while maintaining sensor
performance in both high and low glucose concentration ranges.
[0476] In some alternative embodiments, the exposed surface area of
the working (and/or other) electrode can be increased by altering
the cross-section of the electrode itself. For example, in some
embodiments the cross-section of the working electrode can be
defined by a cross, star, cloverleaf, ribbed, dimpled, ridged,
irregular, or other non-circular configuration; thus, for any
predetermined length of electrode, a specific increased surface
area can be achieved (as compared to the area achieved by a
circular cross-section). Increasing the surface area of the working
electrode can be advantageous in providing an increased signal
responsive to the analyte concentration, which in turn can be
helpful in improving the signal-to-noise ratio, for example.
[0477] In some alternative embodiments, additional electrodes can
be included within the assembly, for example, a three-electrode
system (working, reference, and counter electrodes) and/or an
additional working electrode (e.g., an electrode which can be used
to generate oxygen, which is configured as a baseline subtracting
electrode, or which is configured for measuring additional
analytes). U.S. Patent Publication No. US-2005-0161346-A1, U.S.
Patent Publication No. US-2005-0143635-A1, and U.S. Patent
Publication No. US-2007-0027385-A1 describe some systems and
methods for implementing and using additional working, counter,
and/or reference electrodes. In one implementation wherein the
sensor comprises two working electrodes, the two working electrodes
are juxtapositioned (e.g., extend parallel to each other), around
which the reference electrode is disposed (e.g., helically wound).
In some embodiments wherein two or more working electrodes are
provided, the working electrodes can be formed in a double-,
triple-, quad-, etc. helix configuration along the length of the
sensor (for example, surrounding a reference electrode, insulated
rod, or other support structure). The resulting electrode system
can be configured with an appropriate membrane system, wherein the
first working electrode is configured to measure a first signal
including glucose and baseline (e.g., background noise) and the
additional working electrode is configured to measure a baseline
signal consisting of baseline only (e.g., configured to be
substantially similar to the first working electrode without an
enzyme disposed thereon). In this way, the baseline signal can be
subtracted from the first signal to produce a glucose-only signal
that is substantially not subject to fluctuations in the baseline
and/or interfering species on the signal.
[0478] Although the embodiments of FIGS. 3A to 3C illustrate one
electrode configuration including one bulk metal wire helically
wound around another bulk metal wire, other electrode
configurations are also contemplated. In an alternative embodiment,
the working electrode comprises a tube with a reference electrode
disposed or coiled inside, including an insulator therebetween.
Alternatively, the reference electrode comprises a tube with a
working electrode disposed or coiled inside, including an insulator
therebetween. In another alternative embodiment, a polymer (e.g.,
insulating) rod is provided, wherein the electrodes are deposited
(e.g., electro-plated) thereon. In yet another alternative
embodiment, a metallic (e.g., steel) rod is provided, coated with
an insulating material, onto which the working and reference
electrodes are deposited. In yet another alternative embodiment,
one or more working electrodes are helically wound around a
reference electrode.
[0479] Preferably, the electrodes and membrane systems of the
preferred embodiments are coaxially formed, namely, the electrodes
and/or membrane system all share the same central axle. While not
wishing to be bound by theory, it is believed that a coaxial design
of the sensor enables a symmetrical design without a preferred bend
radius. Namely, in contrast to prior art sensors comprising a
substantially planar configuration that can suffer from regular
bending about the plane of the sensor, the coaxial design of the
preferred embodiments do not have a preferred bend radius and
therefore are not subject to regular bending about a particular
plane (which can cause fatigue failures and the like). However,
non-coaxial sensors can be implemented with the sensor system of
the preferred embodiments.
[0480] 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 the protective slotted sheath is able to insert the
sensor into the catheter and subsequently slide back over the
sensor and release the sensor from the protective slotted sheath,
without complex multi-component designs.
[0481] In one such alternative embodiment, the two wires of the
sensor are held apart and configured for insertion into the
catheter in proximal but separate locations. The separation of the
working and reference electrodes in such an embodiment can provide
additional electrochemical stability with simplified manufacture
and electrical connectivity. One skilled in the art will appreciate
that a variety of electrode configurations can be implemented with
the preferred embodiments.
[0482] In addition to the above-described configurations, the
reference electrode can be separated from the working electrode,
and coiled within a portion of the fluid connector, in some
embodiments. In another embodiment, the reference electrode is
coiled within the fluid connector and adjacent to its first side.
In an alterative embodiment, the reference electrode is coiled
within the fluid connector and adjacent to its second side. In such
embodiments, the reference electrode is in contact with fluid, such
as saline from a saline drip that is flowing into the host, or such
as blood that is being withdrawn from the host. While not wishing
to be bound by theory, this configuration is believed to be
advantageous because the sensor is thinner, allowing the use of
smaller catheters and/or a reduced likelihood to thrombus
production.
[0483] In another embodiment, the reference electrode 346 can be
disposed farther away from the electroactive portion of the working
electrode 343 (e.g., closer to the fluid connector). In some
embodiments, the reference electrode is located proximal to or
within the fluid coupler, such as but not limited to, coiled about
the catheter adjacent to the fluid coupler or coiled within the
fluid coupler and in contact with fluid flowing through the fluid
coupler, such as saline. These configurations can also minimize at
least a portion of the sensor diameter and thereby allow the use of
smaller catheters and reduce the risk of clots.
[0484] In addition to the embodiments described above, the sensor
can be configured with additional working electrodes as described
in U.S. Patent Publication No. US-2005-0143635-A1, U.S. Pat. No.
7,081,195, and U.S. Patent Publication No. US-2007-0027385-A1,
herein incorporated by reference in their entirety. For example, in
one embodiment have an auxiliary working electrode, wherein the
auxiliary working electrode comprises a wire formed from a
conductive material, such as described with reference to the
glucose-measuring working electrode above. Preferably, the
reference electrode, which can function as a reference electrode
alone, or as a dual reference and counter electrode, is formed from
silver, Silver/Silver chloride, and the like.
[0485] In some embodiments, 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 and reference electrode can be helically wound
around the glucose-measuring working electrode. Alternatively, the
auxiliary working electrode and reference electrode can be formed
as a double helix around a length of the glucose-measuring working
electrode. The assembly of wires can then be optionally coated
together with an insulating material, similar to that described
above, in order to provide an insulating attachment. Some portion
of the coated assembly structure is then stripped, for example
using an excimer laser, chemical etching, and the like, to expose
the necessary electroactive surfaces. In some alternative
embodiments, additional electrodes can 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.
[0486] In some alternative embodiments, the sensor is configured as
a dual-electrode system (e.g., FIGS. 2M-2O, 2Q-2S, and 3D-3I)
configured and arranged to detect two analyte and/or configured as
plus-enzyme and minus-enzyme electrodes, as described herein. In
one such dual-electrode system, a first electrode functions as a
hydrogen peroxide sensor including a membrane system containing
glucose-oxidase disposed thereon, which operates as described
herein. A second electrode is a hydrogen peroxide sensor that is
configured similar to the first electrode, but with a modified
membrane system (without active enzyme, for example). This second
electrode provides a signal composed mostly of the baseline signal,
b.
[0487] In some dual-electrode systems, the baseline signal is
(electronically or digitally) subtracted from the glucose signal to
obtain a glucose signal substantially without baseline.
Accordingly, calibration of the resultant difference signal can be
performed by solving the equation y=mx with a single paired
measurement. Calibration of the inserted sensor in this alternative
embodiment can be made less dependent on the values/range of the
paired measurements, less sensitive to error in manual blood
glucose measurements, and can facilitate the sensor's use as a
primary source of glucose information for the user. U.S. Patent
Publication No. US-2005-0143635-A1, U.S. Patent Publication No.
US-2007-0027385-A1, U.S. Patent Publication No. US-2007-0213611-A1,
and U.S. Patent Publication No. US-2008-0083617-A1 each describe
systems and methods for subtracting the baseline from a sensor
signal, each of which is incorporated herein by reference in its
entirety.
[0488] In some alternative dual-electrode system embodiments, the
analyte sensor is configured to transmit signals obtained from each
electrode separately (e.g., without subtraction of the baseline
signal). In this way, the receiver can process these signals to
determine additional information about the sensor and/or analyte
concentration. For example, by comparing the signals from the first
and second electrodes, changes in baseline and/or sensitivity can
be detected and/or measured and used to update calibration (e.g.,
without the use of a reference analyte value). In one such example,
by monitoring the corresponding first and second signals over time,
an amount of signal contributed by baseline can be measured. In
another such example, by comparing fluctuations in the correlating
signals over time, changes in sensitivity can be detected and/or
measured.
[0489] In some embodiments, the reference electrode can be disposed
remotely from the working electrode. In one embodiment, the
reference electrode remains within the fluid flow, but is disposed
within the fluid coupler. For example, the reference electrode can
be coiled within the fluid coupler such that it is contact with
saline flowing into the host, but it is not in physical contact
with the host's blood (except when blood is withdrawn from the
catheter). In another embodiment, the reference electrode is
removed from fluid flow, but still maintains bodily fluid contact.
For example, the reference electrode can be wired to an adhesive
patch that is adhered to the host, such that the reference
electrode is in contact with the host's skin. In yet another
embodiment, the reference electrode can be external from the
system, such as but not limited to in contact with the exterior of
the ex vivo portion of the system, in fluid or electrical contact
with a connected saline drip or other medical device, or in bodily
contact, such as is generally done with EKG electrical contacts.
While not wishing to be bound by theory, it is believed to locating
the reference electrode remotely from the working electrode permits
manufacture of a smaller sensor footprint (e.g., diameter) that
will have relatively less affect on the host's blood flow, such as
less thrombosis, than a sensor having a relatively larger footprint
(e.g., wherein both the working electrode and the reference
electrode are adjacent to each other and within the blood
path).
[0490] In some embodiments of the sensor system, in vivo portion of
the sensor (e.g., the tip 14a) has an enlarged area (e.g., a
bulbous, nail head-shaped, football-shaped, cone-shaped,
cylindrical, etc. portion) as compared a substantial portion of the
sensor (e.g., diameter of the in vivo portion of the sensor). The
sensor tip can be made bulbous by any convenient systems and
methods known in the art, such as but not limited to arc welding,
crimping, smashing, welding, molding, heating, and plasma arc
welding. While not wishing to be bound by theory, it is believed
that an enlarged sensor tip (e.g., bulbous) will prevent vessel
piercing as the sensor is pushed forward into the vessel.
[0491] The sensor of the preferred embodiments is designed with a
minimally invasive architecture so as to minimize reactions or
effects on the blood flow (or on the sensor in the blood flow).
Accordingly, the sensor designs described herein, consider
minimization of dimensions and arrangement of the electrodes and
other components of the sensor system, particularly the in vivo
portion of the sensor (or any portion of the sensor in fluid
contact with the blood flow).
[0492] Accordingly, in some embodiments, a substantial portion of
the in vivo portion of the sensor is designed with at least one
dimension less than about 0.020, 0.015, 0.012, 0.010, 0.008, 0.006,
0.005, 0.004 inches. In some embodiments, a substantial portion of
the sensor that is in fluid contact with the blood flow is designed
with at least one dimension less than about 0.015, 0.012, 0.010,
0.008, 0.006, 0.005, 0.004, 0.003, 0.002, 0.001 inches. As one
exemplary embodiment, a sensor such as described in more detail
with reference to FIGS. 1A to 1C is formed from a 0.004 inch
conductive wire (e.g., platinum) for a diameter of about 0.004
inches along a substantial portion of the sensor (e.g., in vivo
portion or fluid contact portion). As another exemplary embodiment,
a sensor such as described in more detail with reference to FIGS.
1A to 1C is formed from a 0.004 inch conductive wire and vapor
deposited with an insulator material for a diameter of about 0.005
inches along a substantial portion of the sensor (e.g., in vivo
portion or fluid contact portion), after which a desired
electroactive surface area can be exposed. In the above two
exemplary embodiments, the reference electrode can be located
remote from the working electrode (e.g., formed from the conductive
wire). While the devices and methods described herein are directed
to use within the host's blood stream, one skilled in the art will
recognize that the systems, configurations, methods and principles
of operation described herein can be incorporated into other
analyte sensing devices, such as but not limited to subcutaneous
devices or wholly implantable devices such as described in U.S.
Patent Publication No. US-2006-0016700-A1, which is incorporated
herein by reference in its entirety.
[0493] FIG. 3C is a cross section of the sensor shown in FIG. 3B,
taken at line C-C. Preferably, a membrane system (see FIG. 3C) is
deposited over the electroactive surfaces of the sensor and
includes a plurality of domains or layers, such as described in
more detail below, with reference to FIGS. 3B and 3C. The membrane
system can be deposited on the exposed electroactive surfaces using
known thin film techniques (for example, spraying,
electro-depositing, dipping, and the like). In one exemplary
embodiment, each domain is deposited by dipping the sensor into a
solution and drawing out the sensor at a speed that provides the
appropriate domain thickness. In general, the membrane system can
be disposed over (deposited on) the electroactive surfaces using
methods appreciated by one skilled in the art.
[0494] In general, the membrane system includes a plurality of
domains, for example, an electrode domain 347, an interference
domain 348, an enzyme domain 349 (for example, including glucose
oxidase), and a resistance domain 350, as shown in FIG. 3C, 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.
Patent Publication No. US-2005-0245799-A1, and such as is described
in more detail below. The membrane system can be deposited on the
exposed electroactive surfaces using known thin film techniques
(for example, vapor deposition, spraying, electro-depositing,
dipping, and the like). In alternative embodiments, however, other
vapor deposition processes (e.g., physical and/or chemical vapor
deposition processes) can be useful for providing one or more of
the insulating and/or membrane layers, including ultrasonic vapor
deposition, electrostatic deposition, evaporative deposition,
deposition by sputtering, pulsed laser deposition, high velocity
oxygen fuel deposition, thermal evaporator deposition, electron
beam evaporator deposition, deposition by reactive sputtering
molecular beam epitaxy, atmospheric pressure chemical vapor
deposition (CVD), atomic layer CVD, hot wire CVD, low-pressure CVD,
microwave plasma-assisted CVD, plasma-enhanced CVD, rapid thermal
CVD, remote plasma-enhanced CVD, and ultra-high vacuum CVD, for
example. However, the membrane system can be disposed over (or
deposited on) the electroactive surfaces using any known method, as
will be appreciated by one skilled in the art.
[0495] In some embodiments, one or more domains of the membrane
systems are formed from materials such as described above in
connection with the porous layer, 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. Patent Publication
No. US-2005-0245799-A1 describes biointerface and membrane system
configurations and materials that may be applied to the preferred
embodiments.
[0496] Electrode Domain
[0497] In selected embodiments, the membrane system comprises an
electrode domain. The electrode domain 347 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 347 is preferably situated more proximal
to the electroactive surfaces than the interference and/or enzyme
domain. Preferably, the electrode domain includes a coating that
maintains a layer of water at the electrochemically reactive
surfaces of the sensor. In other words, the electrode domain is
present to provide an environment between the surfaces of the
working electrode and the reference electrode, which facilitates an
electrochemical reaction between the electrodes. For example, a
humectant in a binder material can be employed as an electrode
domain; this allows for the full transport of ions in the aqueous
environment. The electrode domain can also assist in stabilizing
the operation of the sensor by accelerating electrode start-up and
drifting problems caused by inadequate electrolyte. The material
that forms the electrode domain can also provide an environment
that protects against pH-mediated damage that can result from the
formation of a large pH gradient due to the electrochemical
activity of the electrodes.
[0498] In one embodiment, the electrode domain 347 includes a
flexible, water-swellable, hydrogel film having a "dry film"
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 3, 2.5, 2, or 1
microns, or less, to about 3.5, 4, 4.5, or 5 microns or more. "Dry
film" thickness refers to the thickness of a cured film cast from a
coating formulation by standard coating techniques.
[0499] In certain embodiments, the electrode domain 347 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 nonionic hydrophilic polyether segments, wherein the
polyurethane polymer is crosslinked with a water-soluble
carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC)) in the presence of polyvinylpyrrolidone and cured at a
moderate temperature of about 50.degree. C.
[0500] In some preferred embodiments, the electrode domain 347 is
formed from a hydrophilic polymer (e.g., a polyamide, a
polylactone, a polyimide, a polylactam, a functionalized polyamide,
a functionalized polylactone, a functionalized polyimide, a
functionalized polylactam or a combination thereof) that renders
the electrode domain substantially more hydrophilic than an
overlying domain, (e.g., interference domain, enzyme domain). In
some embodiments, the electrode domain is formed substantially
entirely and/or primarily from a hydrophilic polymer. In some
embodiments, the electrode domain is formed substantially entirely
from PVP. In some embodiments, the electrode domain is formed
entirely from a hydrophilic polymer. Useful hydrophilic polymers
include but are not limited to poly-N-vinylpyrrolidone (PVP),
poly-N-vinyl-2-piperidone, poly-N-vinyl-2-caprolactam,
poly-N-vinyl-3-methyl-2-caprolactam,
poly-N-vinyl-3-methyl-2-piperidone,
poly-N-vinyl-4-methyl-2-piperidone,
poly-N-vinyl-4-methyl-2-caprolactam,
poly-N-vinyl-3-ethyl-2-pyrrolidone,
poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,
poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,
polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof and
mixtures thereof. A blend of two or more hydrophilic polymers is
preferred in some embodiments. In some preferred embodiments, the
hydrophilic polymer(s) is not crosslinked. In alternative
embodiments, crosslinking is preferred, such as by adding a
crosslinking agent, such as but not limited to EDC, or by
irradiation at a wavelength sufficient to promote crosslinking
between the hydrophilic polymer molecules, which is believed to
create a more tortuous diffusion path through the domain.
[0501] An electrode domain formed from a hydrophilic polymer (e.g.,
PVP) has been shown to substantially reduce break-in time of
analyte sensors; for example, a glucose sensor utilizing a
cellulosic-based interference domain such as described in more
detail elsewhere herein. In some embodiments, a uni-component
electrode domain formed from a single hydrophilic polymer (e.g.,
PVP) has been shown to substantially reduce break-in time of a
glucose sensor to less than about 2 hours, less than about 1 hour,
less than about 20 minutes and/or substantially immediately, such
as exemplified in Examples 9 through 11 and 13. Generally, sensor
break-in is the amount of time required (after implantation) for
the sensor signal to become substantially representative of the
analyte concentration. Sensor break-in includes both membrane
break-in and electrochemical break-in, which are described in more
detail elsewhere herein. In some embodiments, break-in time is less
than about 2 hours. In other embodiments, break-in time is less
than about 1 hour. In still other embodiments, break-in time is
less than about 30 minutes, less than about 20 minutes, less than
about 15 minutes, less than about 10 minutes, or less. In a
preferred embodiment, sensor break-in occurs substantially
immediately. Advantageously, in embodiments wherein the break-in
time is about 0 minutes (substantially immediately), the sensor can
be inserted and begin providing substantially accurate analyte
(e.g., glucose) concentrations almost immediately post-insertion,
for example, wherein membrane break-in does not limit start-up
time.
[0502] While not wishing to be bound by theory, it is believed that
providing an electrode domain that is substantially more
hydrophilic than the next more distal membrane layer or domain
(e.g., the overlaying domain; the layer more distal to the
electroactive surface than the electrode domain, such as an
interference domain or an enzyme domain) reduces the break-in time
of an implanted sensor, by increasing the rate at which the
membrane system is hydrated by the surrounding host tissue. While
not wishing to be bound by theory, it is believed that, in general,
increasing the amount of hydrophilicity of the electrode domain
relative to the overlaying layer (e.g., the distal layer in contact
with electrode domain, such as the interference domain, enzyme
domain, etc.), increases the rate of water absorption, resulting in
reduced sensor break-in time. The hydrophilicity of the electrode
domain can be substantially increased by the proper selection of
hydrophilic polymers, based on their hydrophilicity relative to
each other and relative to the overlaying layer (e.g.,
cellulosic-based interference domain), with preferred polymers
being substantially more hydrophilic than the overlaying layer. In
one exemplary embodiment, PVP forms the electrode domain, the
interference domain is formed from a blend of cellulosic
derivatives, such as but not limited to cellulose acetate butyrate
and cellulose acetate; it is believed that since PVP is
substantially more hydrophilic than the cellulosic-based
interference domain, the PVP rapidly draws water into the membrane
to the electrode domain, and enables the sensor to function with a
desired sensitivity and accuracy and starting within a
substantially reduced time period after implantation. Reductions in
sensor break-in time reduce the amount of time a host must wait to
obtain sensor readings, which is particularly advantageous not only
in ambulatory applications, but particularly in hospital settings
where time is critical.
[0503] While not wishing to be bound by theory, it is believed that
when the water absorption of the overlying domain (e.g., the domain
overlying the electrode domain) is less than the water absorption
of the electrode domain (e.g., during membrane equilibration), then
the difference in water absorption between the two domains will
drive membrane equilibration and thus membrane break-in. Namely,
increasing the difference in hydrophilicity (e.g., between the two
domains) results in an increase in the rate of water absorption,
which, in turn, results in a decrease in membrane break-in time
and/or sensor break-in time. As discussed elsewhere herein, the
relative hydrophilicity of the electrode domain as compared to the
overlying domain can be modulated by a selection of more
hydrophilic materials for formation of the electrode domain (and/or
more hydrophobic materials for the overlying domain(s)). For
example, an electrode domain with hydrophilic polymer capable of
absorbing larger amounts of water can be selected instead of a
second hydrophilic polymer that is capable of absorbing less water
than the first hydrophilic polymer. In some embodiments, the water
content difference between the electrode domain and the overlying
domain (e.g., during or after membrane equilibration) is from about
1% or less to about 90% or more. In other embodiments, the water
content difference between the electrode domain and the overlying
domain is from about 10% or less to about 80% or more. In still
other embodiments, the water content difference between the
electrode domain and the overlying domain is from about 30% or less
to about 60% or more. In preferred embodiments, the electrode
domain absorbs 5 wt. % or less to 95 wt. % or more water,
preferably 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 wt. % to about
55, 60, 65, 70, 75, 80, 85, 90 or 95 wt. % water than the adjacent
(overlying) domain (e.g., the domain that is more distal to the
electroactive surface than the electrode domain).
[0504] In another example, the rate of water absorption by a
polymer can be affected by other factors, such as but not limited
to the polymer's molecular weight. For example, the rate of water
absorption by PVP is dependent upon its molecular weight, which is
typically from about 40 kDa or less to about 360 kDa or more; with
a lower molecular weight PVP (e.g., 40 kDa) absorbing water faster
than a higher molecular weight PVP. Accordingly, modulating
factors, such as molecular weight, that affect the rate of water
absorption by a polymer, can promote the proper selection of
materials for electrode domain fabrication. In one embodiment, a
lower molecular weight PVP is selected, to reduce break-in
time.
[0505] Preferably, the electrode domain is deposited by known thin
film deposition techniques (e.g., spray coating or dip-coating the
electroactive surfaces of the sensor). In some embodiments, the
electrode domain is formed by dip-coating the electroactive
surfaces in an electrode domain solution (e.g., 5, 10, 15, 20, 25
or 30% or more PVP in deionized water) and curing the domain for a
time of from about 15 minutes to about 30 minutes at a temperature
of from about 40.degree. C. to about 55.degree. C. (and can be
accomplished under vacuum (e.g., 20 to 30 mmHg)). In embodiments
wherein dip-coating is used to deposit the electrode domain, a
preferred insertion rate of from about 1 to about 3 inches per
minute into the electrode domain solution, with a preferred dwell
time of from about 0.5 to about 2 minutes in the electrode domain
solution, and a preferred withdrawal rate of from about 0.25 to
about 2 inches per minute from the electrode domain solution
provide a functional coating. However, values outside of those set
forth above can be acceptable or even desirable in certain
embodiments, for example, depending upon solution viscosity and
solution surface tension, as is appreciated by one skilled in the
art. In one embodiment, the electroactive surfaces of the electrode
system are dip-coated one time (one layer) and cured at 50.degree.
C. under vacuum for 20 minutes. In another embodiment, the
electroactive surfaces of the electrode system is dip-coated and
cured at 50.degree. C. under vacuum for 20 minutes a first time,
followed by dip coating and curing at 50.degree. C. under vacuum
for 20 minutes a second time (two layers). In still other
embodiments, the electroactive surfaces can be dip-coated three or
more times (three or more layers). In other embodiments, the 1, 2,
3 or more layers of PVP are applied to the electroactive surfaces
by spray coating or vapor deposition. In some embodiments, a
crosslinking agent (e.g., EDC) can be added to the electrode domain
casting solution to promote crosslinking within the domain (e.g.,
between electrode domain polymer components, latex, etc.). In some
alternative embodiments however, no crosslinking agent is used and
the electrode domain is not substantially crosslinked.
[0506] In some embodiments, the deposited PVP electrode domain 347
has a "dry film" 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.
[0507] Although an independent electrode domain 347 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.
[0508] Interference Domain
[0509] 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 (e.g., a
non-analyte-related signal). This false positive signal causes the
host's analyte concentration (e.g., glucose concentration) to
appear higher than the true analyte concentration. False-positive
signal is a clinically significant problem in some conventional
sensors. For example in a case of a dangerously hypoglycemic
situation, wherein the host has ingested an interferent (e.g.,
acetaminophen), the artificially high glucose signal can lead the
host to believe that he is euglycemic (or, in some cases,
hyperglycemic). As a result, the host can make inappropriate
treatment decisions, such as taking no action, when the proper
course of action is to begin eating. In another example, in the
case of a euglycemic or hyperglycemic situation, wherein a host has
consumed acetaminophen, an artificially high glucose signal caused
by the acetaminophen can lead the host to believe that his or her
glucose concentration is much higher than it truly is. Again, as a
result of the artificially high glucose signal, the host can make
inappropriate treatment decisions, such as giving himself too much
insulin, which in turn can lead to a dangerous hypoglycemic
episode.
[0510] In preferred embodiments, an interference domain 348 is
provided that substantially restricts or blocks the flow of one or
more interfering species therethrough; thereby substantially
preventing artificial signal increases. Some known interfering
species for a glucose sensor, as described in more detail herein,
include acetaminophen, ascorbic acid, bilirubin, cholesterol,
creatinine, dopamine, ephedrine, ibuprofen, L-dopa, methyl dopa,
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 measured species, e.g., the product of an
enzymatic reaction that is measured at the electroactive
surface(s), such as but not limited to H.sub.2O.sub.2.
[0511] In one embodiment, the interference domain 348 is formed
from one or more cellulosic derivatives. Cellulosic derivatives can
include, but are not limited to, cellulose esters and cellulose
ethers. 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, as well
as their copolymers and terpolymers with other cellulosic or
non-cellulosic monomers. Cellulose is a polysaccharide polymer of
.beta.-D-glucose. While cellulosic derivatives are generally
preferred, other polymeric polysaccharides having similar
properties to cellulosic derivatives can also be employed in the
preferred embodiments.
[0512] In one preferred embodiment, the interference domain 348 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. In some embodiments, a blend of two or more cellulose
acetate butyrates having different molecular weights is preferred.
While a "blend" as defined herein (a composition of two or more
substances that are not substantially chemically combined with each
other and are capable of being separated) is generally preferred,
in certain embodiments a single polymer incorporating different
constituents (e.g., separate constituents as monomeric units and/or
substituents on a single polymer chain) can be employed instead.
Additionally, a casting solution or dispersion of cellulose acetate
butyrate at a wt. % of from about 5% to about 25%, preferably from
about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% to about
16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%, and more
preferably from about 5% to about 15% is preferred. Preferably, the
casting solution includes a solvent or solvent system, for example
an acetone:ethanol solvent system. Higher or lower concentrations
can be preferred in certain embodiments. In alternative
embodiments, a single solvent (e.g., acetone) is used to form a
symmetrical membrane domain. A single solvent is used in casting
solutions for forming symmetric membrane layer(s). 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.
[0513] In one alternative embodiment, the interference domain 348
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. In some embodiments, a blend of two or more
cellulose acetates having different molecular weights 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.
[0514] In addition to forming an interference domain from only
cellulose acetate(s) or only cellulose acetate butyrate(s), the
interference domain 348 can be formed from combinations or blends
of cellulosic derivatives, such as but not limited to cellulose
acetate and cellulose acetate butyrate, or combinations of layer(s)
of cellulose acetate and layer(s) of cellulose acetate butyrate. In
some embodiments, a blend of cellulosic derivatives (for formation
of an interference domain) includes up to about 10 wt. % or more of
cellulose acetate. For example, about 1, 2, 3, 4, 5, 6, 7, 8, 9 wt.
% or more cellulose acetate is preferred, in some embodiments. In
some embodiments, the cellulosic derivatives blend includes from
about 90 wt. % or less to about 100 wt. % cellulose acetate
butyrate. For example, in some embodiments, the blend includes
about 91, 92, 93, 94, 95, 96, 97, 98 or 99 wt. % cellulose acetate
butyrate. In some embodiments, the cellulosic derivative blend
includes from about 1.5, 2.0, 2.5, 3.0 or 3.5 wt. % cellulose
acetate to about 98.5, 98.0, 97.5, 97.0 or 96.5 wt. % cellulose
acetate butyrate. In other embodiments, the blend includes from
about 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 or 8 wt. % cellulose acetate
to about 96, 95.5, 95, 94.5, 94, 93.3, 93, 92.5 or 92 wt. %
cellulose acetate butyrate. In still other embodiments, the blend
includes from about 8.5, 9.0, 9.5, 10.0, 10.5 or 11.0 wt. %
cellulose acetate to about 91.5, 91.0, 90.5, 90, 89.5 or 89 wt. %
cellulose acetate butyrate.
[0515] In some embodiments, preferred blends of cellulose acetate
and cellulose acetate butyrate contain from about 1.5 parts or less
to about 60 parts or more cellulose acetate butyrate to one part of
cellulose acetate. In some embodiments, a blend contains from about
2 parts to about 40 parts cellulose acetate butyrate to one part
cellulose acetate. In other embodiments, about 4, 6, 8, 10, 12, 14,
16, 18 or 20 parts cellulose acetate butyrate to one part cellulose
acetate is preferred for formation of the interference domain 348.
In still other embodiments, a blend having from 22, 24, 26, 28, 30,
32, 34, 36 or 38 parts cellulose acetate butyrate to one part
cellulose acetate is preferred. As is discussed elsewhere herein,
cellulose acetate butyrate is relatively more hydrophobic than
cellulose acetate. Accordingly, the cellulose acetate/cellulose
acetate butyrate blend contains substantially more hydrophobic than
hydrophilic components.
[0516] Cellulose acetate butyrate is a cellulosic polymer having
both acetyl and butyl groups, in addition to hydroxyl groups.
Acetyl groups are more hydrophilic than butyl groups, and hydroxyl
groups are more hydrophilic than both acetyl and butyl groups.
Accordingly, the relative amounts of acetyl, butyl and hydroxyl
groups can be used to modulate the hydrophilicity/hydrophobicity of
the cellulose acetate butyrate of the cellulose acetate/cellulose
acetate butyrate blend. A cellulose acetate butyrate can be
selected based on the compound's relative amounts of acetate,
butyrate and hydroxyl groups; and a cellulose acetate can be
selected based on the compounds relative amounts of acetate and
hydroxyl groups. For example, in some embodiments, a cellulose
acetate butyrate having about 35% or less acetyl groups, about 10%
to about 25% butyl groups, and hydroxyl groups making up the
remainder is preferred for formation of the interference domain
348. In other embodiments a cellulose acetate butyrate having from
about 25% to about 34% acetyl groups and from about 15 to about 20%
butyl groups is preferred. In still other embodiments, the
preferred cellulose acetate butyrate contains from about 28% to
about 30% acetyl groups and from about 16 to about 18% butyl
groups. In yet another embodiment, the cellulose acetate butyrate
can have no acetate groups and from about 20% to about 60% butyrate
groups. In yet another embodiment, the cellulose acetate butyrate
has about 55% butyrate groups and no acetate groups.
[0517] While an asymmetric interference domain can be used in some
alternative embodiments, a symmetrical interference domain 348
(e.g., of cellulosic-derivative blends, such as but not limited to
blends of cellulose acetate components and cellulose acetate
butyrate components) is preferred in some embodiments. Symmetrical
membranes are uniform throughout their entire structure, without
gradients of pore densities or sizes, or a skin on one side but not
the other, for example. In various embodiments, a symmetrical
interference domain 348 can be formed by the appropriate selection
of a solvent (e.g., no anti-solvent is used), for making the
casting solution. Appropriate solvents include solvents belonging
to the ketone family that are able to solvate the cellulose acetate
and cellulose acetate butyrate. The solvents include but are not
limited to acetone, methyl ethyl ketone, methyl n-propyl ketone,
cyclohexanone, and diacetone alcohol. Other solvents, such as
furans (e.g., tetra-hydro-furan and 1,4-dioxane), may be preferred
in some embodiments. In one exemplary embodiment, from about 7 wt.
% to about 9 wt. % solids (e.g., a blend of cellulosic derivatives,
such as cellulose acetate and cellulose acetate butyrate) are
blended with a single solvent (e.g., acetone), to form the casting
solution for a symmetrical interference domain. In another
embodiment, from about 10 to about 15% solids are blended with
acetone to form the casting solution. In yet another embodiment,
from about 16 to about 18% solids are blended with acetone to form
the casting solution. A relatively lower or greater weight percent
of solids is preferred to form the casting solution, in some
embodiments.
[0518] The casting solution can be applied either directly to the
electroactive surface(s) of the sensor or on top of an electrode
domain layer (if included in the membrane system). The casting
solution can be applied using any known thin film technique, as
discussed elsewhere herein. Additionally, in various embodiments, a
symmetrical interference domain 348 includes at least one layer;
and in some embodiments, two, three or more layers are formed by
the sequential application and curing of the casting solution.
[0519] The concentration of solids in the casting solution can be
adjusted to deposit a sufficient amount of solids on the electrode
in one layer (e.g., in one dip or spray) to form a membrane layer
with sufficient blocking ability, such that the equivalent glucose
signal of an interferent (e.g., compounds with an oxidation or
reduction potential that overlaps with that of the measured species
(e.g., H.sub.2O.sub.2)), measured by the sensor, is about 60 mg/dL
or less. For example, in some embodiments, the casting solution's
percentage of solids is adjusted such that only a single layer
(e.g., dip one time) is required to deposit a sufficient amount of
the cellulose acetate/cellulose acetate butyrate blend to form a
functional symmetric interference domain that substantially blocks
passage therethrough of at least one interferent, such as but not
limited to acetaminophen, ascorbic acid, dopamine, ibuprofen,
salicylic acid, tolbutamide, tetracycline, creatinine, uric acid,
ephedrine, L-dopa, methyl dopa and tolazamide. In some embodiments,
the amount of interference domain material deposited by as single
dip is sufficient to reduce the equivalent glucose signal of the
interferant (e.g., measured by the sensor) to about 60 mg/dl or
less. In preferred embodiments, the interferent's equivalent
glucose signal response (measured by the sensor) is 50 mg/dl or
less. In more preferred embodiments, the interferent produces an
equivalent glucose signal response of 40 mg/dl or less. In still
more preferred embodiments, the interferent produces an equivalent
glucose signal response of less than about 30, 20 or 10 mg/dl. In
one exemplary embodiment, the interference domain is configured to
substantially block acetaminophen passage therethrough, wherein the
equivalent glucose signal response of the acetaminophen is less
than about 30 mg/dl.
[0520] In alternative embodiments, the interference domain 348 is
configured to substantially block a therapeutic dose of
acetaminophen. The term "therapeutic dose" 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 quantity of any substance required to effect the cure of a
disease, to relieve pain, or that will correct the manifestations
of a deficiency of a particular factor in the diet, such as the
effective dose used with therapeutically applied compounds, such as
drugs. For example, a therapeutic dose of acetaminophen can be an
amount of acetaminophen required to relieve headache pain or reduce
a fever. As a further example, 1,000 mg of acetaminophen taken
orally, such as by swallowing two 500 mg tablets of acetaminophen,
is the therapeutic dose frequently taken for headaches. In some
embodiments, the interference membrane is configured to block a
therapeutic dose of acetaminophen, wherein the equivalent glucose
signal response of the acetaminophen is less than about 60 mg/dl.
In a preferred embodiment, the interference membrane is configured
to block a therapeutic dose of acetaminophen, wherein the
equivalent glucose signal response of the acetaminophen is less
than about 40 mg/dl. In a more preferred embodiment, the
interference membrane is configured to block a therapeutic dose of
acetaminophen, wherein the equivalent glucose signal response of
the acetaminophen is less than about 30 mg/dl.
[0521] While not wishing to be bound by theory, it is believed
that, with respect to symmetrical cellulosic-based membranes, there
is an inversely proportional balance between interferent blocking
and analyte sensitivity. Namely, changes to the interference domain
configuration that increase interferent blocking can result in a
corresponding decrease in sensor sensitivity. Sensor sensitivity is
discussed in more detail elsewhere herein. It is believed that the
balance between interferent blocking and sensor sensitivity is
dependent upon the relative proportions of hydrophobic and
hydrophilic components of the membrane layer (e.g., the
interference domain), with sensors having more hydrophobic
interference domains having increased interferent blocking but
reduces sensitivity; and sensors having more hydrophilic
interference domains having reduced interferent blocking but
increased sensitivity. It is believed that the hydrophobic and
hydrophilic components of the interference domain can be balanced,
to promote a desired level of interferent blocking while at the
same time maintaining a desired level of analyte sensitivity. The
interference domain hydrophobe-hydrophile balance can be
manipulated and/or maintained by the proper selection and blending
of the hydrophilic and hydrophobic interference domain components
(e.g., cellulosic derivatives having acetyl, butyryl, propionyl,
methoxy, ethoxy, propoxy, hydroxyl, carboxymethyl, and/or
carboxyethyl groups). For example, cellulose acetate is relatively
more hydrophilic than cellulose acetate butyrate. In some
embodiments, increasing the percentage of cellulose acetate (or
reducing the percentage of cellulose acetate butyrate) can increase
the hydrophilicity of the cellulose acetate/cellulose acetate
butyrate blend, which promotes increased permeability to
hydrophilic species, such as but not limited to glucose,
H.sub.2O.sub.2 and some interferents (e.g., acetaminophen). In
another embodiment, the percentage of cellulose acetate butyrate is
increased to increase blocking of interferants, but less
permeability to some desired molecules, such as H.sub.2O.sub.2 and
glucose, is also reduced.
[0522] One method, of manipulating the hydrophobe-hydrophile
balance of the interference domain, is to select the appropriate
percentages of acetyl groups (relatively more hydrophilic than
butyl groups), butyl groups (relatively more hydrophobic than
acetyl groups) and hydroxyl groups of the cellulose acetate
butyrate used to form the interference domain 348. For example,
increasing the percentage of acetate groups on the cellulose
acetate butyrate will make the cellulose acetate butyrate more
hydrophilic. In another example, increasing the percentage of butyl
groups on the cellulose acetate butyrate will make the cellulose
acetate butyrate more hydrophobic. In yet another example,
increasing the percentage of hydroxyl groups will increase the
hydrophilicity of the cellulose acetate butyrate. Accordingly, the
selection of a cellulose acetate butyrate that is more or less
hydrophilic (or more or less hydrophobic) can modulate the over-all
hydrophilicity of the cellulose acetate/cellulose acetate butyrate
blend. In one exemplary embodiment, an interference domain can be
configured to be relatively more hydrophobic (and therefore block
interferants more strongly) by reducing the percentage of acetyl or
hydroxyl groups or by increasing the percentage of butyl groups on
the cellulose acetate butyrate used in the casting solution (while
maintaining the relative ratio of cellulose acetate to cellulose
acetate butyrate).
[0523] In some alternative embodiments, the interference domain 348
is formed of a blend of cellulosic derivatives, wherein the
hydrophilic and hydrophobic components of the interference domain
are balanced, such that the glucose sensitivity is from about 1
pA/mg/dL to about 100 pA/mg/dL, and at least one interferent is
sufficiently blocked from passage through the interference domain
such that the equivalent glucose signal response of the at least
one interferent is less than about 60 mg/dL. In a preferred
embodiment, the glucose sensitivity is from about 5 pA/mg/dL to
about 25 pA/mg/dL. In a more preferred embodiments, the glucose
sensitivity is from about 5 pA/mg/dL to about 25 pA/mg/dL and the
equivalent glucose signal response of the at least one interferent
is less than about 40 mg/dL. In a still more preferred embodiments,
the glucose sensitivity is from about 5 pA/mg/dL to about 25
pA/mg/dL and the equivalent glucose signal response of the at least
one interferent is less than about 30 mg/dL. In some embodiments,
the balance between hydrophilic and hydrophobic components of the
interference domain can be achieved by adjusting the amounts of
hydrophilic and hydrophobic components, relative to each other, as
well as adjusting the hydrophilic and hydrophobic groups (e.g.,
acetyl, butyryl, propionyl, methoxy, ethoxy, propoxy, hydroxyl,
carboxymethyl, and/or carboxyethyl groups) of the components
themselves (e.g., cellulosic derivatives, such as but not limited
to cellulose acetate and cellulose acetate butyrate).
[0524] In some alternative embodiments, additional polymers, such
as NAFION.RTM., can be used in combination with cellulosic
derivatives to provide equivalent and/or enhanced function of the
interference domain 348. As one example, a layer of a 5 wt. %
NAFION.RTM. casting solution was applied over a previously applied
(e.g., and cured) layer of 8 wt. % cellulose acetate, e.g., by dip
coating at least one layer of cellulose acetate and subsequently
dip coating at least one layer NAFION.RTM. onto a needle-type
sensor such as described with reference to the preferred
embodiments. Any number of coatings or layers formed in any order
may be suitable for forming the interference domain of the
preferred embodiments.
[0525] In some alternative embodiments, more than one cellulosic
derivative can be used to form the interference domain 348 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(s) (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 for deposition, its desired thickness, and the
like. However, a percent solute of from about 1 wt. % to about 25
wt. % 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 for 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.
[0526] In some alternative embodiments, other polymer types that
can be utilized as a base material for the interference domain 348
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 high molecular weight species. The interference domain 48 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. Pat. No. 7,074,307, U.S. Patent
Publication No. US-2005-0176136-A1, U.S. Pat. No. 7,081,195, and
U.S. Patent Publication No. US-2005-0143635-A1. In some alternative
embodiments, a distinct interference domain is not included.
[0527] In some embodiments, the interference domain 348 is
deposited either directly onto the electroactive surfaces of the
sensor or onto the distal surface of the electrode domain, for a
domain thickness of from about 0.05 micron or less to about 20
microns or more, more preferably from about 0.05, 0.1, 0.15, 0.2,
0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns
to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,
or 19.5 microns, and more preferably still from about 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
[0528] 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 348 is deposited by spray 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 0.5 inch/min to about 60 inches/min,
preferably 1 inch/min, a dwell time of from about 0 minute to about
2 minutes, preferably about 1 minute, and a withdrawal rate of from
about 0.5 inch/minute to about 60 inches/minute, preferably about 1
inch/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.
[0529] In some embodiments, the dip process can be repeated at
least one time and up to 10 times or more. In other embodiments,
only one dip is preferred. 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 certain interferents), and the like. In some
embodiments, 1 to 3 microns may be preferred for the interference
domain thickness; however, values outside of these can be
acceptable or even desirable in certain embodiments, for example,
depending upon viscosity and surface tension, as is appreciated by
one skilled in the art. In one exemplary embodiment, an
interference domain is formed from three layers of cellulose
acetate butyrate. In another exemplary embodiment, an interference
domain is formed from 10 layers of cellulose acetate. In another
embodiment, an interference domain is formed from 1 layer of a
blend of cellulose acetate and 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.
[0530] In some embodiments, the electroactive surface can be
cleaned prior to application of the interference domain 348. In
some embodiments, the interference domain 348 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.
[0531] Enzyme Domain
[0532] In preferred embodiments, the membrane system further
includes an enzyme domain 349 disposed more distally from the
electroactive surfaces than the interference domain 348; however
other configurations can be desirable. 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.
[0533] 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, 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. Patent Publication No. US-2005-0054909-A1.
[0534] In preferred embodiments, the enzyme domain is deposited
onto the interference domain for a domain thickness of from about
0.05 micron or less to about 20 microns or more, more preferably
from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5,
1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more
preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,
4.5, or 5 microns. However in some embodiments, the enzyme domain
can be deposited directly onto the electroactive surfaces.
Preferably, the enzyme domain is deposited by spray or dip coating.
In one embodiment of needle-type (transcutaneous) sensor such as
described herein, the enzyme domain is formed by dip coating the
interference domain coated sensor into an enzyme domain solution
and curing the domain for from about 15 to about 30 minutes at a
temperature of from about 40.degree. C. to about 55.degree. C. (and
can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In
embodiments wherein dip coating is used to deposit the enzyme
domain at room temperature, a preferred insertion rate of from
about 0.25 inch per minute to about 3 inches per minute, with a
preferred dwell time of from about 0.5 minutes to about 2 minutes,
and a preferred withdrawal rate of from about 0.25 inch per minute
to about 2 inches per minute provides a functional coating.
However, values outside of those set forth above can be acceptable
or even desirable in certain embodiments, for example, depending
upon viscosity and surface tension, as is appreciated by one
skilled in the art. In one embodiment, the enzyme domain is formed
by dip coating two times (namely, forming two layers) in an enzyme
domain solution and curing at 50.degree. C. under vacuum for 20
minutes. However, in some embodiments, the enzyme domain can be
formed by dip coating and/or spray coating one or more layers at a
predetermined concentration of the coating solution, insertion
rate, dwell time, withdrawal rate, and/or desired thickness.
[0535] Resistance Domain
[0536] In preferred embodiments, the membrane system includes a
resistance domain 350 disposed more distal from the electroactive
surfaces than the enzyme domain. 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.
[0537] There exists a molar excess of glucose relative to the
amount of oxygen in blood; that is, for every free oxygen molecule
in extracellular fluid, there are typically more than 100 glucose
molecules present (see Updike et al., Diabetes Care
5:207-21(1982)). However, an immobilized enzyme-based glucose
sensor employing oxygen as co-reactant is preferably supplied with
oxygen in non-rate-limiting excess in order for the sensor to
respond linearly to changes in glucose concentration, while not
responding to changes in oxygen concentration. Specifically, when a
glucose-monitoring reaction is oxygen limited, linearity is not
achieved above minimal concentrations of glucose. Without a
semipermeable membrane situated over the enzyme domain to control
the flux of glucose and oxygen, a linear response to glucose levels
can be obtained only for glucose concentrations of up to about 40
mg/dL. However, in a clinical setting, a linear response to glucose
levels is desirable up to at least about 400 mg/dL.
[0538] 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)).
[0539] 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. Patent
Publication No. US-2005-0090607-A1.
[0540] In a preferred embodiment, the resistance domain includes a
polyurethane membrane with both hydrophilic and hydrophobic regions
to control the diffusion of glucose and oxygen to an analyte
sensor, the membrane being fabricated easily and reproducibly from
commercially available materials. A suitable hydrophobic polymer
component is a polyurethane, or polyetherurethaneurea. Polyurethane
is a polymer produced by the condensation reaction of a
diisocyanate and a difunctional hydroxyl-containing material. A
polyurethaneurea is a polymer produced by the condensation reaction
of a diisocyanate and a difunctional amine-containing material.
Preferred diisocyanates include aliphatic diisocyanates containing
from about 4 to about 8 methylene units. Diisocyanates containing
cycloaliphatic moieties can also be useful in the preparation of
the polymer and copolymer components of the membranes of preferred
embodiments. The material that forms the basis of the hydrophobic
matrix of the resistance domain can be any of those known in the
art as appropriate for use as membranes in sensor devices and as
having sufficient permeability to allow relevant compounds to pass
through it, for example, to allow an oxygen molecule to pass
through the membrane from the sample under examination in order to
reach the active enzyme or electrochemical electrodes. Examples of
materials which can be used to make non-polyurethane type membranes
include vinyl polymers, polyethers, polyesters, polyamides,
inorganic polymers such as polysiloxanes and polycarbosiloxanes,
natural polymers such as cellulosic and protein based materials,
and mixtures or combinations thereof.
[0541] 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.
[0542] In some embodiments, the resistance domain is formed from a
silicone polymer modified to allow analyte (e.g., glucose)
transport.
[0543] In some embodiments, the resistance domain is formed from a
silicone polymer/hydrophobic-hydrophilic polymer blend. In one
embodiment, The hydrophobic-hydrophilic polymer for use in the
blend may be any suitable hydrophobic-hydrophilic polymer,
including but not limited to components such as
polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,
polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene
glycol or polypropylene oxide, and copolymers thereof, including,
for example, di-block, tri-block, alternating, random, comb, star,
dendritic, and graft copolymers (block copolymers are discussed in
U.S. Pat. Nos. 4,803,243 and 4,686,044, which are incorporated
herein by reference). In one embodiment, the
hydrophobic-hydrophilic polymer is a copolymer of poly(ethylene
oxide) (PEO) and poly(propylene oxide) (PPO). Suitable such
polymers include, but are not limited to, PEO-PPO diblock
copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO triblock
copolymers, alternating block copolymers of PEO-PPO, random
copolymers of ethylene oxide and propylene oxide, and blends
thereof. In some embodiments, the copolymers may be optionally
substituted with hydroxy substituents. Commercially available
examples of PEO and PPO copolymers include the PLURONIC.RTM. brand
of polymers available from BASF.RTM.. In one embodiment,
PLURONIC.RTM. F-127 is used. Other PLURONIC.RTM. polymers include
PPO-PEO-PPO triblock copolymers (e.g., PLURONIC.RTM. R products).
Other suitable commercial polymers include, but are not limited to,
SYNPERONICS.RTM. products available from UNIQEMA.RTM.. U.S. Patent
Publication No. US-2007-0244379-A1 which is incorporated herein by
reference in its entirety, describes systems and methods suitable
for the resistance and/or other domains of the membrane system of
the preferred embodiments.
[0544] 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.
[0545] In another preferred embodiment, physical vapor deposition
(e.g., ultrasonic vapor deposition) is used for coating one or more
of the membrane domain(s) onto the electrodes, wherein the vapor
deposition apparatus and process include an ultrasonic nozzle that
produces a mist of micro-droplets in a vacuum chamber. In these
embodiments, the micro-droplets move turbulently within the vacuum
chamber, isotropically impacting and adhering to the surface of the
substrate. Advantageously, vapor deposition as described above can
be implemented to provide high production throughput of membrane
deposition processes (e.g., at least about 20 to about 200 or more
electrodes per chamber), greater consistency of the membrane on
each sensor, and increased uniformity of sensor performance, for
example, as described below.
[0546] In some embodiments, depositing the resistance domain (for
example, as described in the preferred embodiments above) includes
formation of a membrane system that substantially blocks or resists
ascorbate (a known electrochemical interferant in hydrogen
peroxide-measuring glucose sensors). While not wishing to be bound
by theory, it is believed that during the process of depositing the
resistance domain as described in the preferred embodiments, a
structural morphology is formed that is characterized in that
ascorbate does not substantially permeate therethrough.
[0547] In a preferred embodiment, the resistance domain is
deposited on the enzyme domain by spray coating a solution of from
about 1 wt. % to about 5 wt. % polymer and from about 95 wt. % to
about 99 wt. % solvent. In spraying a solution of resistance domain
material, including a solvent, onto the enzyme domain, it is
desirable to mitigate or substantially reduce any contact with
enzyme of any solvent in the spray solution that can deactivate the
underlying enzyme of the enzyme domain. Tetrahydrofuran (THF) is
one solvent that minimally or negligibly affects the enzyme of the
enzyme domain upon spraying. Other solvents can also be suitable
for use, as is appreciated by one skilled in the art.
[0548] Although a variety of spraying or deposition techniques can
be used, spraying the resistance domain material and rotating the
sensor at least one time by 180.degree. can typically provide
adequate coverage by the resistance domain. Spraying the resistance
domain material and rotating the sensor at least two times by
120.degree. provides even greater coverage (one layer of
360.degree. coverage), thereby ensuring resistivity to glucose,
such as is described in more detail above.
[0549] In preferred embodiments, the resistance domain is spray
coated and subsequently cured for a time of from about 15 minutes
to about 90 minutes at a temperature of from about 40.degree. C. to
about 60.degree. C. (and can be accomplished under vacuum (e.g.,
from 20 to 30 mmHg)). A cure time of up to about 90 minutes or more
can be advantageous to ensure complete drying of the resistance
domain.
[0550] In one embodiment, the resistance domain is formed by spray
coating at least six layers (namely, rotating the sensor seventeen
times by 120.degree. for at least six layers of 360.degree.
coverage) and curing at 50.degree. C. under vacuum for 60 minutes.
However, the resistance domain can be formed by dip coating or
spray coating any layer or plurality of layers, depending upon the
concentration of the solution, insertion rate, dwell time,
withdrawal rate, and/or the desired thickness of the resulting
film. Additionally, curing in a convention oven can also be
employed.
[0551] In certain embodiments, a variable frequency microwave oven
can be used to cure the membrane domains/layers. In general,
microwave ovens directly excite the rotational mode of solvents.
Consequently, microwave ovens cure coatings from the inside out
rather than from the outside in as with conventional convection
ovens. This direct rotational mode excitation is responsible for
the typically observed "fast" curing within a microwave oven. In
contrast to conventional microwave ovens, which rely upon a fixed
frequency of emission that can cause arcing of dielectric
(metallic) substrates if placed within a conventional microwave
oven, Variable Frequency Microwave (VFM) ovens emit thousands of
frequencies within 100 milliseconds, which substantially eliminates
arcing of dielectric substrates. Consequently, the membrane
domains/layers can be cured even after deposition on metallic
electrodes as described herein. While not wishing to be bound by
theory, it is believe that VFM curing can increase the rate and
completeness of solvent evaporation from a liquid membrane solution
applied to a sensor, as compared to the rate and completeness of
solvent evaporation observed for curing in conventional convection
ovens.
[0552] In certain embodiments, VFM is can be used together with
convection oven curing to further accelerate cure time. In some
sensor applications wherein the membrane is cured prior to
application on the electrode (see, for example, U.S. Patent
Publication No. US-2005-0245799-A1, which is incorporated herein by
reference in its entirety), conventional microwave ovens (e.g.,
fixed frequency microwave ovens) can be used to cure the membrane
layer.
[0553] Treatment of Interference Domain/Membrane System
[0554] Although the above-described methods generally include a
curing step in formation of the membrane system, including the
interference domain, the preferred embodiments further include an
additional treatment step, which can be performed directly after
the formation of the interference domain and/or some time after the
formation of the entire membrane system (or anytime in between). In
some embodiments, the additional treatment step is performed during
(or in combination with) sterilization of the sensor.
[0555] In some embodiments, the membrane system (or interference
domain) is treated by exposure to ionizing radiation, for example,
electron beam radiation, UV radiation, X-ray radiation, gamma
radiation, and the like. Alternatively, the membrane can be exposed
to visible light when suitable photoinitiators are incorporated
into the interference domain. While not wishing to be bound by
theory, it is believed that exposing the interference domain to
ionizing radiation substantially crosslinks the interference domain
and thereby creates a tighter, less permeable network than an
interference domain that has not been exposed to ionizing
radiation.
[0556] In some embodiments, the membrane system (or interference
domain) is crosslinked by forming free radicals, which may include
the use of ionizing radiation, thermal initiators, chemical
initiators, photoinitiators (e.g., UV and visible light), and the
like. Any suitable initiator or any suitable initiator system can
be employed, for example, .alpha.-hydroxyketone,
.alpha.-aminoketone, ammonium persulfate (APS), redox systems such
as APS/bisulfite, or potassium permanganate. Suitable thermal
initiators include but are not limited to potassium persulfate,
ammonium persulfate, sodium persulfate, and mixtures thereof.
[0557] In embodiments wherein electron beam radiation is used to
treat the membrane system (or interference domain), a preferred
exposure time is from about 6k or 12 kGy to about 25 or 50 kGy,
more preferably about 25 kGy. However, one skilled in the art
appreciates that choice of molecular weight, composition of
cellulosic derivative (or other polymer), and/or the thickness of
the layer can affect the preferred exposure time of membrane to
radiation. Preferably, the exposure is sufficient for substantially
crosslinking the interference domain to form free radicals, but
does not destroy or significantly break down the membrane or does
not significantly damage the underlying electroactive surfaces.
[0558] In embodiments wherein UV radiation is employed to treat the
membrane, UV rays from about 200 nm to about 400 nm are preferred;
however values outside of this range can be employed in certain
embodiments, dependent upon the cellulosic derivative and/or other
polymer used.
[0559] In some embodiments, for example, wherein photoinitiators
are employed to crosslink the interference domain, one or more
additional domains can be provided adjacent to the interference
domain for preventing delamination that may be caused by the
crosslinking treatment. These additional domains can be "tie
layers" (i.e., film layers that enhance adhesion of the
interference domain to other domains of the membrane system). In
one exemplary embodiment, a membrane system is formed that includes
the following domains: resistance domain, enzyme domain, electrode
domain, and cellulosic-based interference domain, wherein the
electrode domain is configured to ensure adhesion between the
enzyme domain and the interference domain. In embodiments wherein
photoinitiators are employed to crosslink the interference domain,
UV radiation of greater than about 290 nm is preferred.
Additionally, from about 0.01 to about 1 wt % photoinitiator is
preferred weight-to-weight with a preselected cellulosic polymer
(e.g., cellulose acetate); however values outside of this range can
be desirable dependent upon the cellulosic polymer selected.
[0560] In general, sterilization of the transcutaneous sensor can
be completed after final assembly, utilizing methods such as
electron beam radiation, gamma radiation, glutaraldehyde treatment,
and the like. The sensor can be sterilized prior to or after
packaging. In an alternative embodiment, one or more sensors can be
sterilized using variable frequency microwave chamber(s), which can
increase the speed and reduce the cost of the sterilization
process. In another alternative embodiment, one or more sensors can
be sterilized using ethylene oxide (EtO) gas sterilization, for
example, by treating with 100% ethylene oxide, which can be used
when the sensor electronics are not detachably connected to the
sensor and/or when the sensor electronics must undergo a
sterilization process. In one embodiment, one or more packaged sets
of transcutaneous sensors (e.g., 1, 2, 3, 4, or 5 sensors or more)
are sterilized simultaneously.
[0561] Therapeutic Agents
[0562] A variety of therapeutic (bioactive) agents can be used with
the analyte sensor system of the preferred embodiments, such as the
analyte sensor system of the embodiments shown in FIGS. 1A-3C. In
some embodiments, the therapeutic agent is an anticoagulant. The
term "anticoagulant" 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 substance
the prevents coagulation (e.g., minimizes, reduces, or stops
clotting of blood). In some embodiments, an anticoagulant is
included in the analyte sensor system to prevent coagulation within
or on the sensor (e.g., within or on the catheter or within or on
the sensor). Suitable anticoagulants for incorporation into the
sensor system include, but are not limited to, vitamin K
antagonists (e.g., Acenocoumarol, Clorindione, Dicumarol
(Dicoumarol), Diphenadione, Ethyl biscoumacetate, Phenprocoumon,
Phenindione, Tioclomarol, or Warfarin), heparin group
anticoagulants (e.g., Platelet aggregation inhibitors: Antithrombin
III, Bemiparin, Dalteparin, Danaparoid, Enoxaparin, Heparin,
Nadroparin, Parnaparin, Reviparin, Sulodexide, Tinzaparin), other
platelet aggregation inhibitors (e.g., Abciximab, Acetylsalicylic
acid (Aspirin), Aloxiprin, Beraprost, Ditazole, Carbasalate
calcium, Cloricromen, Clopidogrel, Dipyridamole, Epoprostenol,
Eptifibatide, Indobufen, Iloprost, Picotamide, Ticlopidine,
Tirofiban, Treprostinil, Triflusal), enzymes (e.g., Alteplase,
Ancrod, Anistreplase, Brinase, Drotrecogin alfa, Fibrinolysin,
Protein C, Reteplase, Saruplase, Streptokinase, Tenecteplase,
Urokinase), direct thrombin inhibitors (e.g., Argatroban,
Bivalirudin, Desirudin, Lepirudin, Melagatran, Ximelagatran, other
antithrombotics (e.g., Dabigatran, Defibrotide, Dermatan sulfate,
Fondaparinux, Rivaroxaban) and the like.
[0563] In one embodiment, heparin is incorporated into the analyte
sensor system. In a further embodiment, heparin is coated on the
catheter (inner and/or outer diameter) and/or sensor, for example,
by dipping or spraying. While not wishing to be bound by theory, it
is believed that heparin coated on the catheter and/or sensor
prevents aggregation and clotting of blood on the analyte sensor
system, thereby preventing thromboembolization (e.g., prevention of
blood flow by the thrombus or clot) and/or subsequent
complications. In another embodiment, an antimicrobial is coated on
the catheter (inner and/or outer diameter) and/or sensor.
[0564] In some embodiments, the therapeutic agent is an
antimicrobial. The term "antimicrobial agent" as used in the
preferred embodiments means antibiotics, antiseptics, disinfectants
and synthetic moieties, and combinations thereof, that are soluble
in organic solvents such as alcohols, ketones, ethers, aldehydes,
acetonitrile, acetic acid, methylene chloride and chloroform.
[0565] Classes of antibiotics that can be used include
tetracyclines (i.e. minocycline), rifamycins (i.e. rifampin),
macrolides (i.e. erythromycin), penicillins (i.e. nafeillin),
cephalosporins (i.e. cefazolin), other beta-lactam antibiotics
(i.e. imipenem, aztreonam), aminoglycosides (i.e. gentamicin),
chloramphenicol, sufonamides (i.e. sulfamethoxazole), glycopeptides
(i.e. vancomycin), quinolones (i.e. ciprofloxacin), fusidic acid,
trimethoprim, metronidazole, clindamycin, mupirocin, polyenes (i.e.
amphotericin B), azoles (i.e. fluconazole) and beta-lactam
inhibitors (i.e. sulbactam).
[0566] Examples of specific antibiotics that can be used include
minocycline, rifampin, erythromycin, nafcillin, cefazolin,
imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin,
ciprofloxacin, trimethoprim, metronidazole, clindamycin,
teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin,
lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin,
pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin,
tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,
amphotericin B, fluconazole, itraconazole, ketoconazole, and
nystatin.
[0567] Examples of antiseptics and disinfectants are
hexachlorophene, cationic bisiguanides (i.e. chlorhexidine,
cyclohexidine) iodine and iodophores (i.e. povidoneiodine),
para-chloro-meta-xylenol, triclosan, furan medical preparations
(i.e. nitrofurantoin, nitrofurazone), methenamine, aldehydes
(glutaraldehyde, formaldehyde) and alcohols. Other examples of
antiseptics and disinfectants will readily suggest themselves to
those of ordinary skill in the art.
[0568] These antimicrobial agents can be used alone or in
combination of two or more of them. The antimicrobial agents can be
dispersed throughout the material of the sensor and/or catheter.
The amount of each antimicrobial agent used to impregnate the
medical device varies to some extent, but is at least of an
effective concentration to inhibit the growth of bacterial and
fungal organisms, such as staphylococci, gram-positive bacteria,
gram-negative bacilli and Candida.
[0569] In some embodiments, the membrane system of the preferred
embodiments preferably include a bioactive agent, which is
incorporated into at least a portion of the membrane system, or
which is incorporated into the device and adapted to diffuse
through the membrane.
[0570] There are a variety of systems and methods by which the
bioactive agent is incorporated into the membrane of the preferred
embodiments. In some embodiments, the bioactive agent is
incorporated at the time of manufacture of the membrane system. For
example, the bioactive agent can be blended prior to curing the
membrane system, or subsequent to membrane system manufacture, for
example, by coating, imbibing, solvent-casting, or sorption of the
bioactive agent into the membrane system. Although the bioactive
agent is preferably incorporated into the membrane system, in some
embodiments the bioactive agent can be administered concurrently
with, prior to, or after insertion of the device intravascularly,
for example, by oral administration, or locally, for example, by
subcutaneous injection near the implantation site. A combination of
bioactive agent incorporated in the membrane system and bioactive
agent administration locally and/or systemically can be preferred
in certain embodiments.
[0571] In general, a bioactive agent can be incorporated into the
membrane system, and/or incorporated into the device and adapted to
diffuse therefrom, in order to modify the tissue response of the
host to the membrane. In some embodiments, the bioactive agent is
incorporated only into a portion of the membrane system adjacent to
the sensing region of the device, over the entire surface of the
device except over the sensing region, or any combination thereof,
which can be helpful in controlling different mechanisms and/or
stages of thrombus formation. In some alternative embodiments
however, the bioactive agent is incorporated into the device
proximal to the membrane system, such that the bioactive agent
diffuses through the membrane system to the host circulatory
system.
[0572] The bioactive agent can include a carrier matrix, wherein
the matrix includes one or more of collagen, a particulate matrix,
a resorbable or non-resorbable matrix, a controlled-release matrix,
and/or a gel. In some embodiments, the carrier matrix includes a
reservoir, wherein a bioactive agent is encapsulated within a
microcapsule. The carrier matrix can include a system in which a
bioactive agent is physically entrapped within a polymer network.
In some embodiments, the bioactive agent is cross-linked with the
membrane system, while in others the bioactive agent is sorbed into
the membrane system, for example, by adsorption, absorption, or
imbibing. The bioactive agent can be deposited in or on the
membrane system, for example, by coating, filling, or solvent
casting. In certain embodiments, ionic and nonionic surfactants,
detergents, micelles, emulsifiers, demulsifiers, stabilizers,
aqueous and oleaginous carriers, solvents, preservatives,
antioxidants, or buffering agents are used to incorporate the
bioactive agent into the membrane system. The bioactive agent can
be incorporated into a polymer using techniques such as described
above, and the polymer can be used to form the membrane system,
coatings on the membrane system, portions of the membrane system,
and/or any portion of the sensor system.
[0573] The membrane system can be manufactured using techniques
known in the art. The bioactive agent can be sorbed into the
membrane system, for example, by soaking the membrane system for a
length of time (for example, from about an hour or less to about a
week or more, preferably from about 4, 8, 12, 16, or 20 hours to
about 1, 2, 3, 4, 5, or 7 days).
[0574] The bioactive agent can be blended into uncured polymer
prior to forming the membrane system. The membrane system is then
cured and the bioactive agent thereby cross-linked and/or
encapsulated within the polymer that forms the membrane system.
[0575] In yet another embodiment, microspheres are used to
encapsulate the bioactive agent. The microspheres can be formed of
biodegradable polymers, most preferably synthetic polymers or
natural polymers such as proteins and polysaccharides. As used
herein, the term polymer is used to refer to both to synthetic
polymers and proteins. U.S. Pat. No. 6,281,015, which is
incorporated herein by reference in its entirety, discloses some
systems and methods that can be used in conjunction with the
preferred embodiments. In general, bioactive agents can be
incorporated in (1) the polymer matrix forming the microspheres,
(2) microparticle(s) surrounded by the polymer which forms the
microspheres, (3) a polymer core within a protein microsphere, (4)
a polymer coating around a polymer microsphere, (5) mixed in with
microspheres aggregated into a larger form, or (6) a combination
thereof. Bioactive agents can be incorporated as particulates or by
co-dissolving the factors with the polymer. Stabilizers can be
incorporated by addition of the stabilizers to the factor solution
prior to formation of the microspheres.
[0576] The bioactive agent can be incorporated into a hydrogel and
coated or otherwise deposited in or on the membrane system. Some
hydrogels suitable for use in the preferred embodiments include
cross-linked, hydrophilic, three-dimensional polymer networks that
are highly permeable to the bioactive agent and are triggered to
release the bioactive agent based on a stimulus.
[0577] The bioactive agent can be incorporated into the membrane
system by solvent casting, wherein a solution including dissolved
bioactive agent is disposed on the surface of the membrane system,
after which the solvent is removed to form a coating on the
membrane surface.
[0578] The bioactive agent can be compounded into a plug of
material, which is placed within the device, such as is described
in U.S. Pat. Nos. 4,506,680 and 5,282,844, which are incorporated
herein by reference in their entirety. In some embodiments, it is
preferred to dispose the plug beneath a membrane system; in this
way, the bioactive agent is controlled by diffusion through the
membrane, which provides a mechanism for sustained-release of the
bioactive agent in the host.
[0579] Release of Bioactive Agents
[0580] Numerous variables can affect the pharmacokinetics of
bioactive agent release. The bioactive agents of the preferred
embodiments can be optimized for short- and/or long-term release.
In some embodiments, the bioactive agents of the preferred
embodiments are designed to aid or overcome factors associated with
short-term effects (e.g., acute inflammation and/or thrombosis) of
sensor insertion. In some embodiments, the bioactive agents of the
preferred embodiments are designed to aid or overcome factors
associated with long-term effects, for example, chronic
inflammation or build-up of fibrotic tissue and/or plaque material.
In some embodiments, the bioactive agents of the preferred
embodiments combine short- and long-term release to exploit the
benefits of both.
[0581] As used herein, "controlled," "sustained," or "extended"
release of the factors can be continuous or discontinuous, linear
or non-linear. This can be accomplished using one or more types of
polymer compositions, drug loadings, selections of excipients or
degradation enhancers, or other modifications, administered alone,
in combination or sequentially to produce the desired effect.
[0582] Short-term release of the bioactive agent in the preferred
embodiments generally refers to release over a period of from about
a few minutes or hours to about 2, 3, 4, 5, 6, or 7 days or
more.
[0583] Loading of Bioactive Agents
[0584] The amount of loading of the bioactive agent into the
membrane system can depend upon several factors. For example, the
bioactive agent dosage and duration can vary with the intended use
of the membrane system, for example, the intended length of use of
the device and the like; differences among patients in the
effective dose of bioactive agent; location and methods of loading
the bioactive agent; and release rates associated with bioactive
agents and optionally their carrier matrix. Therefore, one skilled
in the art will appreciate the variability in the levels of loading
the bioactive agent, for the reasons described above.
[0585] In some embodiments, wherein the bioactive agent is
incorporated into the membrane system without a carrier matrix, the
preferred level of loading of the bioactive agent into the membrane
system can vary depending upon the nature of the bioactive agent.
The level of loading of the bioactive agent is preferably
sufficiently high such that a biological effect (e.g., thrombosis
prevention) is observed. Above this threshold, bioactive agent can
be loaded into the membrane system so as to imbibe up to 100% of
the solid portions, cover all accessible surfaces of the membrane,
and/or fill up to 100% of the accessible cavity space. Typically,
the level of loading (based on the weight of bioactive agent(s),
membrane system, and other substances present) is from about 1 ppm
or less to about 1000 ppm or more, preferably from about 2, 3, 4,
or 5 ppm up to about 10, 25, 50, 75, 100, 200, 300, 400, 500, 600,
700, 800, or 900 ppm. In certain embodiments, the level of loading
can be 1 wt. % or less up to about 50 wt. % or more, preferably
from about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 wt. % up to about
25, 30, 35, 40, or 45 wt. %.
[0586] When the bioactive agent is incorporated into the membrane
system with a carrier matrix, such as a gel, the gel concentration
can be optimized, for example, loaded with one or more test
loadings of the bioactive agent. It is generally preferred that the
gel contain from about 0.1 or less to about 50 wt. % or more of the
bioactive agent(s), preferably from about 0.2, 0.3, 0.4, 0.5, 0.6,
0.7, 0.8, or 0.9 wt. % to about 6, 7, 8, 9, 10, 15, 20, 25, 30, 35,
40, or 45 wt. % or more bioactive agent(s), more preferably from
about 1, 2, or 3 wt. % to about 4 or 5 wt. % of the bioactive
agent(s). Substances that are not bioactive can also be
incorporated into the matrix.
[0587] Referring now to microencapsulate bioactive agents, the
release of the agents from these polymeric systems generally occurs
by two different mechanisms. The bioactive agent can be released by
diffusion through aqueous filled channels generated in the dosage
form by the dissolution of the agent or by voids created by the
removal of the polymer solvent or a pore forming agent during the
original micro-encapsulation. Alternatively, release can be
enhanced due to the degradation of the encapsulating polymer. With
time, the polymer erodes and generates increased porosity and
microstructure within the device. This creates additional pathways
for release of the bioactive agent.
[0588] In some embodiments, the sensor is designed to be bioinert,
e.g., by the use of bioinert materials. Bioinert materials do not
substantially cause any response from the host. As a result, cells
can live adjacent to the material but do not form a bond with it.
Bioinert materials include but are not limited to alumina,
zirconia, titanium oxide or other bioinert materials generally used
in the "catheter/catheterization" art. While not wishing to be
bound by theory, it is believed that inclusion of a bioinert
material in or on the sensor can reduce attachment of blood cells
or proteins to the sensor, thrombosis or other host reactions to
the sensor.
[0589] Dual-Electrode Analyte Sensors
[0590] In general, electrochemical analyte sensors provide at least
one working electrode and at least one reference electrode, which
are configured to generate a signal associated with a concentration
of the analyte in the host, such as described herein, and as
appreciated by one skilled in the art. The output signal is
typically a raw data stream that is used to provide a useful value
of the measured analyte concentration in a host to the patient or
doctor, for example. However, the analyte sensors of the preferred
embodiments may further measure at least one additional signal. For
example, in some embodiments, the additional signal is associated
with the baseline and/or sensitivity of the analyte sensor, thereby
enabling monitoring of baseline and/or sensitivity changes that may
occur in a continuous analyte sensor over time.
[0591] In preferred embodiments, the analyte sensor comprises a
first working electrode E1 and a second working electrode E2, in
addition to a reference electrode, which is referred to as a
dual-electrode system herein. The first and second working
electrodes may be in any useful conformation, as described in U.S.
Patent Publication No. US-2007-0027385-A1, U.S. Patent Publication
No. US-2007-0213611-A1, U.S. Patent Publication No.
US-2007-0027284-A1, U.S. Patent Publication No. US-2007-0032717-A1,
U.S. Patent Publication No. US-2007-0093704-A1, and U.S. Patent
Publication No. US-2008-0083617-A1, each of which is incorporated
herein by reference in its entirety. In some preferred embodiments,
the first and second working electrodes are twisted and/or bundled.
For example, two wire working electrodes can be twisted together,
such as in a helix conformation. The reference electrode can then
be wrapped around the twisted pair of working electrodes. In some
preferred embodiments, the first and second working electrodes
include a coaxial configuration. A variety of dual-electrode system
configurations are described with reference to FIGS. 7A1 through 11
of the references incorporated above. In some embodiments, the
sensor is configured as a dual electrode sensor, such as described
in U.S. Patent Publication No. US-2005-0143635-A1, U.S. Patent
Publication No. US-2007-0027385-A1, U.S. Patent Publication No.
US-2007-0213611-A1, and U.S. Patent Publication No.
US-2008-0083617-A1, each of which is incorporated herein by
reference in its entirety. However, a dual-electrode system can be
provided in any planar or non-planar configuration, such as can be
appreciated by one skilled in the art, and can be found in U.S.
Pat. Nos. 6,175,752, 6,579,690, 6,484,046, 6,512,939, 6,477,395,
6,424,847, 6,212,416, 6,119,028, 6,400,974, 6,595,919, 6,141,573,
6,122,536; European Patent Publication No. EP 1153571, U.S. Pat.
Nos. 6,512,939, 5,605,152, 4,431,004, 4,703,756, 6,514,718,
5,985,129, PCT Patent Publication No. WO04/021877, U.S. Pat. Nos.
5,494,562, 6,120,676, and 6,542,765, each of which are incorporated
in there entirety herein by reference in their entirety. In
general, it is understood that the disclosed embodiments are
applicable to a variety of continuous analyte measuring device
configurations
[0592] FIG. 3D illustrates a dual-electrode system in preferred
embodiments. The dual-electrode sensor system includes a first
working electrode E1 and the second working electrode E2, both of
which are disposed beneath a sensor membrane M02, such as but not
limited to a membrane system similar to that described with
reference to FIG. 3C and/or FIGS. 3F through 3I. The first working
electrode E1 is disposed beneath an active enzymatic portion M04 of
the sensor membrane M02, which includes an enzyme configured to
detect the analyte or an analyte-related compound. Accordingly, the
first working electrode E1 is configured to generate a first signal
composed of both signal related to the analyte and signal related
to non-analyte electroactive compounds (e.g., physiological
baseline, interferents, and non-constant noise) that have an
oxidation/reduction potential that overlaps with the
oxidation/reduction potential of the analyte. This
oxidation/reduction potential may be referred to as a "first
oxidation/reduction potential" herein. The second working electrode
E2 is disposed beneath an inactive-enzymatic or non-enzymatic
portion M06 of the sensor membrane M02. The non-enzymatic portion
M06 of the membrane includes either an inactivated form of the
enzyme contained in the enzymatic portion M04 of the membrane or no
enzyme. In some embodiments, the non-enzymatic portion M06 can
include a non-specific protein, such as BSA, ovalbumin, milk
protein, certain polypeptides, and the like. The non-enzymatic
portion M06 generates a second signal associated with noise of the
analyte sensor. The noise of the sensor comprises signal
contribution due to non-analyte electroactive species (e.g.,
interferents) that have an oxidation/reduction potential that
substantially overlaps the first oxidation/reduction potential
(e.g., that overlap with the oxidation/reduction potential of the
analyte). In some embodiments of a dual-electrode analyte sensor
configured for fluid communication with a host's circulatory
system, the non-analyte 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.
[0593] In one exemplary embodiment, the dual-electrode analyte
sensor is a glucose sensor having a first working electrode E1
configured to generate a first signal associated with both glucose
and non-glucose related electroactive compounds that have a first
oxidation/reduction potential. Non-glucose related electroactive
compounds can be any compound, in the sensor's local environment
that has an oxidation/reduction potential substantially overlapping
with the oxidation/reduction potential of H.sub.2O.sub.2, for
example. While not wishing to be bound by theory, it is believed
that the glucose-measuring electrode can measure both the signal
directly related to the reaction of glucose with GOx (produces
H.sub.2O.sub.2 that is oxidized at the working electrode) and
signals from unknown compounds that are in the blood 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 known that blood chemistry changes dramatically during/after a
heart attack (e.g., pH changes, changes in the concentration of
various blood components/protein, and the like). Additionally, a
variety of medicaments or infusion fluid components (e.g.,
acetaminophen, ascorbic acid, dopamine, ibuprofen, salicylic acid,
tolbutamide, tetracycline, creatinine, uric acid, ephedrine,
L-dopa, methyl dopa and tolazamide) that may be given to the host
may have oxidation/reduction potentials that overlap with that of
H.sub.2O.sub.2.
[0594] In this exemplary embodiment, the dual-electrode analyte
sensor includes a second working electrode E2 that is configured to
generate a second signal associated with the non-glucose related
electroactive compounds that have the same oxidation/reduction
potential as the above-described first working electrode (e.g.,
para supra). In some embodiments, the non-glucose related
electroactive species includes at least one of interfering species,
non-reaction-related H.sub.2O.sub.2, and other electroactive
species. For example, interfering species includes any compound
that is not directly related to the electrochemical signal
generated by the glucose-GOx reaction, such as but not limited to
electroactive species in the local environment produces by other
bodily processes (e.g., cellular metabolism, a disease process, and
the like). Other electroactive species includes any compound that
has an oxidation/reduction potential similar to or overlapping that
of H.sub.2O.sub.2.
[0595] 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, and interference domain
of the membrane described elsewhere herein) such that the first and
second electrodes are influenced by substantially the same
external/environmental factors, which enables substantially
equivalent measurement of both the constant and non-constant
species/noise. This advantageously allows the substantial
elimination of noise 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, medicaments, pH
fluctuations, O.sub.2 fluctuations, or the like) known to effect
the accuracy of conventional continuous sensor signals. Preferably,
the sensor includes electronics operably connected to the first and
second working electrodes. The electronics are configured to
provide the first and second signals that are used to generate
glucose concentration data substantially without signal
contribution due to non-glucose-related noise. Preferably, the
electronics include at least a potentiostat that provides a bias to
the electrodes. In some embodiments, sensor electronics are
configured to measure the current (or voltage) to provide the first
and second signals. The first and second signals are used to
determine the glucose concentration substantially without signal
contribution due to non-glucose-related noise such as by but not
limited to subtraction of the second signal from the first signal
or alternative data analysis techniques. In some embodiments, the
sensor electronics include a transmitter that transmits the first
and second signals to a receiver, where additional data analysis
and/or calibration of glucose concentration can be processed. U.S.
Patent Publication No. US-2005-0027463-A1, U.S. Patent Publication
No. US-2005-0203360-A1 and U.S. Patent Publication No.
US-2006-0036142-A1 describe systems and methods for processing
sensor analyte data and are incorporated herein by reference in
their entirety.
[0596] In preferred embodiments, the dual-electrode sensor is
configured such that the first and second working electrodes E1, E2
are equivalently influenced by in vivo environmental factors. For
example, in one embodiment, the dual-electrode sensor is configured
for fluid communication with the circulatory system of the host,
such as by implantation in the host's vein or artery via a vascular
access device (also referred to as a fluid communication device
herein) such as a catheter and/or cannula. When the sensor is
contacted with a sample of the host's circulatory system (e.g.,
blood), the first and second working electrodes E1, E2 are
configured such that they are equivalently influenced by a variety
of environmental factors impinging upon the sensor, such as but not
limited to non-analyte related electroactive species (e.g.,
interfering species, non-reaction-related H.sub.2O.sub.2, an other
electroactive species). Because the first and second working
electrodes are equivalently influenced by in vivo environmental
factors, the signal component associated with the in vivo
environmental factors (e.g., non-analyte related species with an
oxidation/reduction potential that overlaps with that of the
analyte) can be removed from the signal detected by the first
working electrode (e.g., the first signal). This can give a
substantially analyte-only signal. The effects of in vivo
environmental factors upon the dual-electrode system are discussed
in greater detail elsewhere herein with reference to FIGS.
3G-3I.
[0597] In preferred embodiments, the dual-electrode sensor includes
electronics (e.g., a processor module, processing memory) that are
operably connected to the first and second working electrodes and
are configured to provide the first and second signals to generate
analyte concentration data substantially without signal
contribution due to non-analyte-related noise. For example, the
sensor electronics process and/or analyze the signals from the
first and second working electrodes and calculate the portion of
the first electrode signal that is due to analyte concentration
only. The portion of the first electrode signal that is not due to
the analyte concentration can be considered to be background, such
as but not limited to noise. Accordingly, in one embodiment of a
dual-electrode sensor system configured for fluid communication
with a host's circulatory system (e.g., via a vascular access
device) the system comprising electronics operably connected to the
first and second working electrodes; the electronics are configured
to process the first and second signals to generate analyte
concentration data substantially without signal contribution due to
noise.
[0598] As a non-limiting example, FIG. 3E illustrates one preferred
embodiment, the dual-electrode analyte sensor. In this embodiment,
the sensor comprises a first working electrode E1 configured to
detect the analyte and a second working electrode E2, wherein the
first and second working electrodes are formed of two wire working
electrodes twisted together to form a "twisted pair." The first
working electrode E1 is disposed beneath an enzymatic portion of
the membrane (not shown) containing an analyte-detecting enzyme.
For example, in a glucose-detecting dual-electrode analyte sensor,
a glucose-detecting enzyme, such as GOX, is included in the
enzymatic portion of the membrane. Accordingly, the first working
electrode E1 detects signal due to both the analyte and
non-analyte-related species that have an oxidation/reduction
potential that substantially overlaps with the oxidation/reduction
potential of the analyte. The second working electrode E2 is
disposed beneath a portion of the membrane comprising either
inactivated enzyme (e.g., inactivated by heat, chemical or UV
treatment) or no enzyme. Accordingly, the second working electrode
E2 detects a signal associated with only the non-analyte
electroactive species that have an oxidation/reduction potential
that substantially overlaps with that of analyte. For example, in
the glucose-detecting dual-electrode analyte sensor described
above, the non-analyte (e.g., non-glucose) electroactive species
have an oxidation/reduction potential that overlaps substantially
with that of H.sub.2O.sub.2. A reference electrode R, such as a
silver/silver chloride wire electrode, is wrapped around the
twisted pair. The three electrodes E1, E2 and R are connected to
sensor electronics (not shown), such as described elsewhere herein.
In preferred embodiments, the dual-electrode sensor is configured
to provide an analyte-only signal (e.g., glucose-only signal)
substantially without a signal component due to the non-analyte
electroactive species (e.g., noise). For example, the
dual-electrode sensor is operably connected to sensor electronics
that process the first and second signals, such that a
substantially analyte-only signal is provided (e.g., output to a
user). In other exemplary embodiments, the dual-electrode sensor
can be configured for detection of a variety of analytes other than
glucose, such as but not limited to urea, creatinine, succinate,
glutamine, oxygen, electrolytes, cholesterol, lipids,
triglycerides, hormones, liver enzymes, and the like.
[0599] 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 the 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. 3E, the
surface area of the reference electrode (e.g., R) includes the
exposed surface of the reference electrode, such as but not limited
to the electrode surface facing away from the working electrodes
E1, E2.
[0600] 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. Alternative
dual-electrode configurations include those illustrated in FIGS.
2G-2S, as described herein.
[0601] 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.
[0602] As a non-limiting example, dual-electrode glucose sensor can
be manufactured as follows. In one embodiment, the working
electrodes are first coated with a layer of insulating material
(e.g., non-conductive material or dielectric) to prevent direct
contact between the working electrodes E1, E2 and the reference
electrode R. At this point, or at any point hereafter, the two
working electrodes can be twisted and/or bundled to form a twisted
pair. A portion of the insulator 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 working 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 by 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 (e.g., electrodes, E1, temporarily
covered with a UV-blocking material); irradiating the sensor with
UV light (e.g., 254-320 nm; a wavelength that inactivates the
enzyme, such as by cross-linking amino acid residues) and removing
the mask. Accordingly, the GOx on E2 is inactivated by the UV
treatment, but the E1 GOx is still active due to the protective
mask. In other embodiments, an enzyme solution containing active
enzyme is applied to a first electroactive surface (e.g., E1) and
an enzyme solution containing either inactivated enzyme or no
enzyme is applied to the second electroactive surface (e.g., E2).
Thus, 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.
[0603] In some circumstances, cross talk can interfere with
analyte/noise detection. In general, cross talk occurs when signal
(e.g., in the form of energy and/or a detectable species such as
but not limited to H.sub.2O.sub.2) is transferred from one
electrode (e.g., the first working electrode) to another (e.g., the
second working electrode), and detected as a signal by the other
electrode. To prevent cross talk, in preferred embodiments, the
first and second working electrodes E1, E2 are separated by
diffusion barrier, such as an insulator, a non-conductive material,
a reference electrode and/or the like.
[0604] FIG. 3F illustrates the use of a diffusion barrier to
prevent cross talk in a dual-electrode glucose sensor, in one
embodiment. The first and second working electrodes E1, E2 are
disposed beneath a membrane 348 and separated by a diffusion
barrier D. Within the membrane, glucose is metabolized by the GOx
enzyme, which produces H.sub.2O.sub.2. The H.sub.2O.sub.2 produced
by the enzymatic reaction can diffuse in any direction through the
membrane 348. A portion of the H.sub.2O.sub.2 diffuses to the
surface of the first working electrode and is detected due to the
transfer of two electrons to the electrode. Another portion of the
H.sub.2O.sub.2 can diffuse out of the membrane. Since the diffusion
barrier D is disposed between the working electrodes, the diffusion
barrier substantially blocks diffusion of H.sub.2O.sub.2 to the
second working electrode E2. If no diffusion barrier were present,
the H.sub.2O.sub.2 would be able to diffuse to the second working
electrode E2 and cause a signal also referred to as cross talk. A
variety of diffusion barriers can be employed to prevent cross
talk. In some embodiments, the diffusion barrier D is a physical
diffusion barrier, such as a structure between the working
electrodes that blocks glucose and H.sub.2O.sub.2 from diffusing
from the first working electrode E1 to the second working electrode
E2. In other embodiments, the diffusion barrier D is a spatial
diffusion barrier, such as a distance between the working
electrodes that blocks glucose and H.sub.2O.sub.2 from diffusing
from the first working electrode E1 to the second working electrode
E2. In still other embodiments, the diffusion barrier D is a
temporal diffusion barrier, such as a period of time between the
activity of the working electrodes such that if glucose or
H.sub.2O.sub.2 diffuses from the first working electrode E1 to the
second working electrode E2, the second working electrode E2 will
not substantially be influenced by the H.sub.2O.sub.2 from the
first working electrode E1.
[0605] Accordingly, in some preferred embodiments, the
dual-electrode sensor comprises an insulator, such as an electrical
insulator, located between the first and second working electrodes,
wherein the insulator comprises a physical diffusion barrier. The
physical diffusion barrier is configured to structurally block a
substantial amount of diffusion of at least one of an analyte
(e.g., glucose) and a co-analyte (e.g., H.sub.2O.sub.2) between the
first and second working electrodes. In some embodiments, the
diffusion barrier comprises a structure that protrudes from a plane
that intersects both the first and second working electrodes. In a
further embodiment, the structure that protrudes comprises an
electrical insulator and/or an electrode.
[0606] In some preferred embodiments, the dual-electrode sensor
comprises an insulator located between the first and second working
electrodes, wherein the insulator comprises a diffusion barrier
configured to substantially block diffusion of at least one of an
analyte and a co-analyte between the first and second working
electrodes. In preferred embodiments, 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.
[0607] In still other preferred embodiments, the dual-electrode
sensor comprises a sensor membrane configured to substantially
block diffusion of at least one of an analyte and a co-analyte
between the first and second working electrodes by a discontinuity
of the sensor membrane between the first and second working
electrodes. A discontinuity of the sensor membrane is a type of
physical diffusion barrier formed by a portion of the membrane
between the two working electrodes, in some embodiments, wherein a
discontinuity in the membrane structure blocks diffusion of
H.sub.2O.sub.2 between the electrodes. Discontinuities of sensor
membranes are discussed in greater detail with reference to FIG.
3I, in the section entitled "Sensor Configurations for Equivalent
Measurement of Noise."
[0608] In some embodiments, the dual-electrode sensor system is
configured for fluid communication with a host's circulatory
system, such as via a vascular access device. A variety of vascular
access devices suitable for use with a dual-electrode analyte
sensor are described elsewhere herein. In some embodiments, the
vascular access device comprises a lumen and at least a portion of
the sensor is disposed within the lumen; and in some embodiments,
at least a portion of the sensor can extend into the vascular
system. In some embodiments, the vascular access device comprises a
hub and the continuous analyte sensor is disposed substantially
within the hub. In some embodiments, the system includes a fluid
coupler configured and arranged to mate with the vascular access
device on a first end; wherein the sensor is disposed within a
portion of the fluid coupler and/or at a surface of the fluid
coupler. In some embodiments, the sensor is configured to reside
substantially above a plane defined by the host's skin. In some
embodiments, the sensor is disposed on a surface of the vascular
access device. In some embodiments, the vascular access device is
configured for insertion into at least one of an artery, a vein, a
fistula, and an extracorporeal circulatory device configured to
circulate at least a portion of the host's blood outside of the
host's body. In some embodiments, the system includes a flow
control device in fluid communication with the vascular access
device. The flow control device is configured to meter a flow of a
fluid (e.g., blood, saline, a reference solution) through the
vascular access device. In some embodiments, the flow control
device is further configured to control fluid contact with the
continuous analyte sensor, as is described in the section entitled
"Integrated Sensor System."
[0609] In preferred embodiments, the sensor electronics (e.g.,
electronic components) are operably connected to the first and
second working electrodes. The electronics are configured to
calculate at least one analyte sensor data point. For example, the
electronics can include a potentiostat, A/D converter, RAM, ROM,
transmitter, and the like. In some embodiments, the potentiostat
converts the raw data (e.g., raw counts) collected from the sensor
to a value familiar to the host and/or medical personnel. For
example, the raw counts from a glucose sensor can be converted to
milligrams of glucose per deciliter of glucose (e.g., mg/dl). In
some embodiments, the electronics are operably connected to the
first and second working electrodes and are configured to process
the first and second signals to generate a glucose concentration
substantially without signal contribution due to non-glucose noise
artifacts. The sensor electronics determine the signals from
glucose and non-glucose related signal with an overlapping
measuring potential (e.g., from a first working electrode) and then
non-glucose related signal with an overlapping measuring potential
(e.g., from a second electrode). The sensor electronics then use
these data to determine a substantially glucose-only concentration,
such as but not limited to subtracting the second electrode's
signal from the first electrode's signal, to give a signal (e.g.,
data) representative of substantially glucose-only concentration,
for example. In general, the sensor electronics may perform
additional operations, such as but not limited to data smoothing
and noise analysis.
[0610] In preferred embodiments, the dual-electrode sensor includes
electronics (e.g., a processor module, processing memory) that are
operably connected to the first and second working electrodes and
are configured to provide the first and second signals to generate
an analyte concentration data substantially without signal
contribution due to non-analyte-related noise. For example, the
sensor electronics process and/or analyze the signals from the
first and second working electrodes and calculate the portion of
the first electrode signal that is due to analyte concentration
only. The portion of the first electrode signal that is not due to
the analyte concentration can be considered to be background, such
as but not limited to noise. Accordingly, in one embodiment of a
dual-electrode sensor system configured for fluid communication
with a host's circulatory system (e.g., via a vascular access
device) the system comprising electronics operably connected to the
first and second working electrodes; the electronics are configured
to process the first and second signals to generate analyte
concentration data substantially without signal contribution due to
noise.
[0611] In some embodiments, the dual-electrode analyte sensor
includes a reference sensor/system, as described elsewhere therein,
whereby reference data can be provided for calibration (e.g.,
internal to the system), without the use of an external (e.g.,
separate from the system) analyte-measuring device. In an exemplary
embodiment, the dual-electrode sensor is a glucose sensor and
external glucose data points (e.g., from a hand-held glucose meter
or a YSI device) are not required for calibration of a
dual-electrode glucose sensor system that includes a reference
sensor. In some embodiments, the reference sensor is configured to
be disposed within the same local environment as the dual-electrode
analyte sensor, such that the reference sensor and the
dual-electrode analyte sensor can be simultaneously exposed to a
sample. In some embodiments, the reference sensor/system can be
disposed remotely from the dual-electrode sensor. In these
embodiments, the electronics module is configured to process the
reference data with the first and second signals to generate
analyte concentration data substantially without signal
contribution due to noise. In some embodiments, the electronics
module is configured to calibrate the dual-electrode analyte sensor
data using the reference sensor data, as described elsewhere
herein.
[0612] In some embodiments, the electronics module is configured to
determine a scaling factor (k) as described in the section entitled
"Calibration Systems and Methods." Briefly, a scaling factor
defines a relationship between the enzymatic portion of the
membrane and the non-enzymatic portion of the membrane.
Accordingly, in some embodiments, the electronics module, also
referred to as the processor module herein, is configured to and/or
comprises programming to calibrate the analyte sensor data using
the scaling factor, such that the calibrated sensor data does not
include inaccuracies that can arise due to small differences
between the plus- and minus-enzyme portions of the membrane at the
first and second working electrodes, respectively.
[0613] In some embodiments, the system is configured to calibrate
the continuous dual-electrode analyte sensor using a reference
fluid (e.g., 602a), as described in the section entitled
"integrated sensor system." In some embodiments, the system is
configured to calibrate the sensor using single-point calibration,
in other embodiments, the system is configured to calibrate the
sensor without a reference data point provided by an external
analyte monitor (e.g., SMBG, YSI), as described elsewhere herein.
In some embodiments, the system includes a reference sensor
configured to generate a signal associated with a reference analyte
in the sample (e.g., internal to the system), wherein the
continuous analyte sensor is further configured to generate a third
signal associated with the reference analyte, and wherein the
system is configured to calibrate the continuous analyte sensor
using the reference signal and the third signal. In some
embodiments, the reference sensor comprises an optical sensing
apparatus, such as but not limited to an optical O.sub.2 sensor. In
preferred embodiments, the continuous analyte sensor is a glucose
sensor. In other embodiments, a substantial portion of the
continuous analyte sensor has a diameter of less than about 0.008
inches, as is described elsewhere herein.
[0614] In some further embodiments, the continuous analyte sensor
further comprises a bioinert material or a bioactive agent
incorporated therein or thereon. Applicable bioactive agent include
but are not limited to vitamin K antagonists, heparin group
anticoagulants, platelet aggregation inhibitors, enzymes, direct
thrombin inhibitors, Dabigatran, Defibrotide, Dermatan sulfate,
Fondaparinux, and Rivaroxaban.
[0615] As a non-limiting example, in some preferred embodiments, a
method for continuously detecting an analyte in the host in vivo
using a dual-electrode analyte sensor is provided. In some
embodiments, a vascular access device (e.g., a catheter) is
inserted into the host's circulatory system, such as into a vein or
artery. The sensor is contacted with a sample of the circulatory
system, such as a sample of blood withdrawn into the catheter. A
first signal is generated by the sensor, wherein the first signal
is associated with associated with the analyte and non-analyte
related electroactive compounds having a first oxidation/reduction
potential in a sample of the circulatory system of the host. In
preferred embodiments, the analyte sensor is configured to detect
glucose. A second signal is also generated, wherein the second
signal is associated with noise of the analyte sensor, wherein the
noise comprises signal contribution due to non-analyte related
electroactive species with an oxidation/reduction potential that
substantially overlaps with the first oxidation/reduction potential
in the sample. The first and second signals are processed to
provide a processed signal substantially without a signal component
associated with noise. In some embodiments, the first and second
signals are processed to provide a scaling factor, which can then
be used to calibrate the first signal. In some embodiments, a
reference sensor is also contacted with the sample, and a third
signal associated with a reference analyte generated. In some
embodiments, the reference sensor is an optical detection
apparatus, such as but not limited to an optical O.sub.2 sensor. In
this embodiment, the first and second signals can be calibrated
using the third and/or reference signal. In some preferred
embodiments, the processing step comprises evaluating steady-state
information and transient information, wherein the first and second
signals each comprise steady-state and transient information. In
some further embodiments, the evaluating step includes evaluating
at least one of sensitivity information and baseline information,
wherein the steady-state information comprises the sensitivity and
baseline information.
[0616] Optical Detection
[0617] In some embodiments, the continuous analyte sensor is
configured to detect the analyte by optical means. In some
embodiments, various types of Raman and/or fluorescent
spectroscopic detection are used. For example, glucose can be
detected via fiber optic visible fluorescence, using glucose
dehydrogenase (GDH) and a modified flavin adenine dinucleotide
(FAD) coenzyme system, Concanavalin A, or hexokinase. In some
embodiments, a fluorescent molecule (e.g., a fluorophore) is
attached to the co-enzyme or to a hydrogen peroxide end-product
reactant, as in a colorimetric detection system. In an alternative
embodiment, ferrocene is modified and used as a mediator in the
reaction of GOX (or GHD) with glucose, wherein a pH-sensitive
fluorophore is used to detect the reaction. In some embodiments,
fiber optic probes are constructed by applying membrane systems
configured for optical/fluorescent detection to an optical fiber.
In some embodiments, multiple fiber optic probes are bundled, which
enables a variety of integrative and/or subtractive signal
correlations/corrections and to enhance error detection. Examples
of optical detection can be found in U.S. Pat. Nos. 7,289,836 and
7,149,562, each of which is incorporated by reference herein in its
entirety.
[0618] Sensor Signal Generation
[0619] In some embodiments, a continuous analyte detection system
is provided, including a sensor configured and arranged for fluid
contact with a host's circulatory system and a processor module.
The sensor comprises both a continuous analyte sensor (e.g., either
non-dual-electrode or dual-electrode) and a reference sensor. For
example, in some embodiments the system includes a continuous
analyte sensor including a working electrode and a reference
electrode, and a reference sensor. In other embodiments, the system
includes a dual-electrode analyte sensor, including first and
second working electrodes and a reference electrode, and a
reference sensor. The continuous analyte sensor is configured and
arranged to generate a first signal associated with a test analyte
and a second signal associated with a reference analyte. For
example, in one embodiment, the test analyte is glucose and the
reference analyte is oxygen; thus, the first signal is associated
with glucose and the reference signal is associated with oxygen.
The reference sensor is configured to generate a reference signal
that is also associated with the reference analyte. In general, a
"reference analyte" can be any analyte that can be measured by both
the analyte sensor and the reference sensor, such those analytes
listed under the definition of "analyte" in the section entitled
"Definitions." In preferred embodiments, the reference analyte is
one that is relatively stable within the host's body, such as but
not limited to O.sub.2, succinate, glutamine, and the like. In this
embodiment, the processor module is configured to and/or comprises
programming to process the second signal (e.g., related to the
reference analyte) and the reference signal to calibrate the first
signal (e.g., related to the analyte). In some embodiments, the
processor module calibrates the second signal (e.g., the reference
analyte signal detected by the analyte sensor) using the reference
signal provided by the reference sensor, and then to calibrate the
first signal (e.g., the analyte signal) using the second
signal.
[0620] As a non-limiting example, in some embodiments, the system's
continuous analyte sensor is a dual-electrode sensor that comprises
both first and second working electrodes E1, E2. Accordingly, the
first working electrode is disposed beneath an active enzymatic
portion of a sensor membrane and generates a signal (e.g., the
first signal) associated with both the analyte (e.g., glucose) and
non-analyte related electroactive compounds (e.g., non-glucose
compounds that have an oxidation/reduction potential that
substantially overlaps with the oxidation/reduction potential of
glucose). Additionally, the second working is disposed beneath an
inactive-enzymatic or a non-enzymatic portion of the sensor
membrane and generates a non-analyte-related signal associated with
the non-analyte electroactive species. In this embodiment, the
processor module configured to and/or comprises programming to
process signals from the first and second working electrodes, and
to thereby generate a first signal substantially without a
non-analyte signal component.
[0621] The second signal (e.g., related to the reference analyte)
can be generated by various means. For example, in some
embodiments, the first working electrode of the dual-electrode
analyte sensor is configured to generate both the first signal and
the second signal. For example, in some embodiments, pulsed
amperometric detection, including switching, cycling or pulsing the
voltage of the electrode in an electrochemical system (e.g.,
between a positive voltage (e.g., +0.6 for detecting glucose) and a
negative voltage (e.g., -0.6 for detecting oxygen)) can be employed
to determine an oxygen measurement. For example, the first working
electrode is configured to generate a signal associated with the
analyte when a potential of +0.6 mV is applied thereto. If the
potential is switch to -0.6 mV, then the first working electrode
becomes an O.sub.2 sensor and measures a signal associate with the
amount of O.sub.2 passing through the sensor's membrane system.
U.S. Pat. No. 4,680,268, which is incorporated by reference herein,
described pulsed amperometric detection in greater detail.
Additional oxygen sensors are described in U.S. Pat. No. 6,512,939,
which is incorporated herein by reference.
[0622] As a non-limiting example, in one embodiment the
dual-electrode analyte sensor is a glucose sensor configured for
fluid communication with a host's circulatory system, wherein the
sensor is configured to generate a first signal associated with
glucose (at the first working electrode E1) at an applied potential
of 0.6 mV, and then to generate a second signal associated with
O.sub.2 (also at the first working electrode E1) at an applied
potential of -0.6 mV. Thus, in some embodiments, the potential
applied to the first working electrode can be switched from +0.6 mV
to -0.6 mV, such that the first working electrode switches from
measuring the analyte-related signal (e.g., glucose) to measuring
the second signal (e.g., associated with O.sub.2).
[0623] In some alternative embodiments, the second working
electrode E2 (e.g., instead of the first working electrode E1) is
configured to generate the second signal. As a non-limiting
example, in another embodiment the dual-electrode analyte sensor is
a glucose sensor configured for fluid communication with a host's
circulatory system, wherein the sensor is configured to generate a
first signal associated with glucose (at the first working
electrode E1) at an applied potential of 0.6 mV, to generate a
non-analyte-related signal (at the second working electrode E2) at
an applied potential of 0.6 mV, and then to generate a second
signal associated with O.sub.2 (also at the second working
electrode E2) at an applied potential of -0.6 mV. Thus, in some
embodiments, the potential applied to the second working electrode
can be switched from 0.6 mV to -0.6 mV, such that the second
working electrode switches from measuring the non-analyte-related
signal to measuring the second signal (e.g., associated with
O.sub.2).
[0624] In still other embodiments, the second signal can be
generated by a third working electrode disposed beneath the
sensor's membrane. As a non-limiting example, in another embodiment
the dual-electrode analyte sensor is a glucose sensor configured
for fluid communication with a host's circulatory system, wherein
the sensor is configured to generate a first signal associated with
glucose (at the first working electrode E1) at an applied potential
of 0.6 mV, to generate a non-analyte-related signal (at the second
working electrode E2) at an applied potential of 0.6 mV, and then
to generate the second signal associated with O.sub.2 (at the third
working electrode, e.g., E3, not shown) at an applied potential of
-0.6 mV. Thus, in some embodiments, switching the applied potential
from 0.6 mV to -0.6 mV is not required.
[0625] As described above, the system includes a reference sensor.
In some embodiments, the reference sensor is an optical sensing
apparatus, as described above. In other embodiments, the reference
sensor is configured to detect the reference analyte by any means
known in the art, such as but not limited to electrochemical,
chemical, physical, immunochemical, calorimetric and/or radiometric
means. Preferably, the reference sensor is disposed in the same
local environment as the continuous analyte sensor, but not under
the membrane system of the continuous analyte sensor. For example,
the reference sensor can be disposed adjacent to the continuous
analyte sensor, such that when the continuous analyte sensor is
contacted with a sample the reference sensor is simultaneously
contacted by the sample. As a non-limiting example, in some
embodiments, a dual-electrode continuous analyte sensor and a
reference sensor are disposed adjacently, such that they can be
simultaneously exposed to a sample of the host's circulatory
system.
[0626] As a non-limiting example, in some embodiments, a
dual-electrode sensor includes a first working electrode configured
to detect the analyte (including non-analyte-related noise) and a
second working electrode is configured to detect the signal
associated with non-analyte-related noise. In some embodiments, the
first and second working electrodes are bundled and/or twisted, and
the reference sensor is disposed adjacent to the first and second
working electrodes. In some embodiments, either the first or the
second working electrodes of the dual-electrode sensor is
configured to detect a signal associated with the reference analyte
(e.g., a second signal); while in other embodiments, the
dual-electrode sensor includes a third working electrode configured
to detect the reference analyte (e.g., the second signal).
[0627] As a non-limiting example, in one embodiment of a system
comprising both a dual-electrode sensor and an optical reference
sensor, the dual-electrode sensor is both a glucose sensor and an
O.sub.2 sensor, and the reference sensor is an optical O.sub.2
sensor. Accordingly, as described elsewhere herein, the first
working electrode of the dual-electrode sensor is configured to
detect a signal associated with both glucose and
non-glucose-related electroactive species (in a sample of the
host's circulatory system), and the second working electrode is
configured to detect the non-glucose related electroactive species.
Either the first working electrode or the second working electrode
is configured to detect O.sub.2, such as via switching the applied
potential from 0.6 mV to -0.6 MV, as described elsewhere herein.
The reference sensor, which can be bundled with the dual-electrode
sensor, is configured to optically detect a reference signal
associated with the O.sub.2 concentration of the sample. In some
embodiments, instead of using the first or second working
electrodes to detect O.sub.2, the dual-electrode sensor includes a
third electrode configured to detect O.sub.2.
[0628] In preferred embodiments, the signal related to a reference
analyte (e.g., O.sub.2) can be used to calibrate the signals from a
continuous analyte sensor, such as in the event of a drift in
sensor sensitivity and/or baseline. Accordingly, the signals
related to the reference analyte, from the continuous analyte and
reference sensors, can be processed to determine a calibration
factor. The calibration factor can then be used to calibrate the
continuous analyte sensor data. As used herein, the term
"calibration factor" 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
mathematical function generated by processing the reference
analyte-related signal of the continuous analyte sensor and the
reference analyte-related signal of the reference sensor, which can
be used to calibrate the continuous analyte sensor data initially
and/or responsive to an occurrence of a drift in sensor sensitivity
and/or baseline.
[0629] In some embodiments, a method for measuring an analyte in a
host is provided. First, a continuous analyte detection system,
which includes a continuous analyte sensor and a reference sensor,
is provided. In preferred embodiments, the continuous analyte
sensor is configured and arranged to generate a first signal
associated with a test analyte (e.g., glucose) and a second signal
associated with a reference analyte (e.g., O.sub.2), and the
reference sensor configured to generate a reference signal
associated with the reference analyte (e.g., O.sub.2).
[0630] Next, the detection system is exposed to a sample of a
host's circulatory system in vivo. For example, the detection
system can be fluidly coupled to a vascular access device implanted
in a host's circulatory system, such that a sample of the host's
blood can be drawn back an contacted with the detection system.
Preferably, the continuous analyte sensor and the reference sensor
are exposed to the sample simultaneously. Accordingly, measurements
of the reference analyte can be made at the same time by the
continuous analyte and reference sensors. In some embodiments, a
fluid flow device configured for fluid communication with the
circulatory system of the host and to meter a flow of a fluid
therethrough is provided. In these embodiments, the fluid flow
device comprises a vascular access device configured for insertion
into either an artery or a vein of the host. Such fluid flow
devices are described in detail in the sensor entitled "Integrated
Sensor System." In preferred embodiments, the fluid flow device is
coupled with the continuous analyte detection system, and a sample
of the circulatory system of the host is withdrawn. In some
preferred embodiments, the fluid flow device is further configured
to meter the flow of a non-bodily fluid through the vascular access
device. Non-bodily fluids include a variety of sterile infusion
fluids, such as but are not limited to saline, reference solutions
such as a glucose solution of defined concentration, nutritional
supplements, IV medicaments, and the like.
[0631] When the sample contacts the system, signals are received
from the continuous analyte sensor and the reference sensor. The
signals received include a first signal (e.g., related to the test
analyte, such as but not limited to glucose), a second signal
(e.g., related to the reference analyte, such as but not limited to
O.sub.2) and a reference signal (e.g., related to the reference
analyte). In some embodiments, the first signal is received from a
first working electrode disposed under an enzymatic portion of a
membrane system. For example, in the case of a glucose detection
system, the first working electrode is disposed beneath a portion
of the membrane system including active GOX and detects a first
signal associated with the concentration of glucose in the sample.
In some embodiments, the first working electrode also received the
second signal, as described elsewhere herein. In other embodiments,
the second signal is received from a second working electrode that
is also disposed under the membrane system. In some embodiments,
the second working electrode configured to also receive a
non-analyte-related signal. For example, the second working
electrode is disposed under a non-enzymatic portion of the membrane
system, in some embodiments. In some other embodiments, the
non-analyte-related signal is received from a third working
electrode disposed under a non-enzymatic portion of the membrane
system. In some embodiments, the reference sensor is configured to
detect the reference analyte optically. For example, in some
embodiments, the reference analyte is oxygen. Accordingly, the
second signal and the reference signal received are associated with
the concentration of oxygen in the sample.
[0632] After the signals have been received, a calibration factor
is calculated, wherein the calibration factor is associated with a
sensitivity and/or baseline of the continuous analyte sensor. For
example, in some embodiments, the continuous analyte detection
system is exposed to a bodily fluid (e.g., blood) and the
calculating step includes comparing steady-state information of the
first signal and steady-state information of the second signal. In
some embodiments, the calibration factor can be calculated by
examining the transient information of the first and second
signals.
[0633] In some other embodiments, the continuous analyte detection
system is configured to be exposed to a non-bodily fluid, such as
saline or a reference fluid, such as to wash the previous blood
sample off of the device. During the washing procedure, the
non-bodily fluid can be held substantially stagnant (e.g., no flow
or very little flow of the fluid past the sensor) for a period of
time. During this period of time, the working electrodes of the
continuous analyte sensor detect signals associated with
non-analyte-related compounds diffusion to the first and second
working electrodes. For example, in some embodiments, a saline
solution containing a defined amount of glucose is used to wash the
sensor. When the glucose-containing saline is held stagnant (e.g.,
after washing the previous sample off of the sensor), the GOX at
the first working electrode metabolizes glucose diffusing through
the membrane. As the glucose is metabolized, the reactant (e.g.,
H.sub.2O.sub.2) begins to accumulate and produce signals at both
the first and second working electrodes. As a result, the signal
increase on each of the first and second working electrodes (e.g.,
during the time period) can be compared to calculate the
calibration factor. This method for calculating the calibration
factor is discussed in greater detail elsewhere herein, with
reference to FIGS. 3J and 3K.
[0634] After the calibration factor has been calculated, the
signal(s) from the continuous analyte sensor are calibrated using
the calibration factor. The process of calculating the calibration
factor and then using the newly calculated calibration factor to
calibrate the signals can be continuous, continual and/or
intermittent; such that at time passes the calibration factor and
calibration are updated. Thus, the system is configured to evaluate
changes in membrane sensitivity and/or baseline, to adjust the
calculation of analyte concentrations accordingly, whereby the host
is provided with more accurate data for use in therapy
decision-making.
[0635] Multi-Sensor Apparatus
[0636] In some preferred embodiments, a multi-sensor apparatus
configured for the detection of a plurality of analytes in a
circulatory system of a host in vivo is provided. FIGS. 2G through
2S illustrate some exemplary embodiments of such a device. In
preferred embodiments, the multi-sensor apparatus is a vascular
access device (e.g., a catheter) or a connector configured for
fluid communication with the circulatory system of the host.
Preferably, the multi-sensor apparatus includes a lumen (e.g., a
duct) sufficiently large to house the plurality of sensors, as
described elsewhere herein. In an exemplary embodiment, the
multi-sensor apparatus comprises a plurality of analyte sensors,
wherein the plurality of analyte sensor are configured to detect at
least one analyte and to contact a sample of the host's circulatory
system. In one exemplary embodiment, the multi-sensor apparatus
comprises a lumen, an external surface, and two orifices, wherein a
first orifice is proximal relative to the host and the second
orifice is distal. In some embodiments, such as in a catheter, the
proximal orifice is referred to herein as the in vivo orifice and
the distal orifice is referred to as the ex vivo orifice.
Preferably, at least the distal orifice is configured to couple
with a fluid flow device (or a component thereof), such as but not
limited to a connector or coupler, a valve, IV tubing, a pump, and
the like. For example, in an embodiment wherein the multi-sensor
apparatus is a catheter, the distal orifice (e.g., the ex vivo
orifice) is configured to couple to IV tubing, various types of IV
connectors, and the like. In some embodiments, both the proximal
and distal orifices are configured to couple with IV equipment. For
example, in an embodiment wherein the multi-sensor apparatus is
configured as a connector (e.g., a Leur lock) the proximal orifice
is configured to couple with a vascular access device (e.g., a
catheter/cannula), IV tubing, and/or other connectors, and the
distal end is configured to couple with a fluid flow device (e.g.,
IV tubing, a pump, etc.). Preferably; a plurality of analyte
sensors are disposed within the lumen of the multi-sensor
apparatus. For example, 2, 3, 4, 5, 6, 7, or more sensors can be
disposed within the lumen of the multi-sensor apparatus. In some
embodiments, each of the plurality of analyte sensor is configured
to detect a different analyte. In some embodiments, two or more of
the plurality of analyte sensors are configured to detect the same
analyte, thereby providing redundancy and/or fail-safes in analyte
detection and/or sensor function.
[0637] FIG. 2G provides an exemplary embodiment of a multi-sensor
apparatus, namely a catheter, including an in vivo portion
configured for insertion into the host and an ex vivo portion 218
(e.g., a connector or hub) configured to remain outside the host's
body after implantation/insertion of the in vivo portion into a
host. The in vivo portion may also be referred to as the proximal
portion/end of the catheter (e.g., with respect to the host)
includes an in vivo orifice at or near the catheter's tip, for
fluid communication with the host's circulatory system upon
implantation into the host's vein or artery, or in an
extracorporeal circulatory device. The ex vivo portion of the
catheter may also be referred to as the proximal portion (e.g.,
with respect to the host). A plurality of analyte sensors 240 are
disposed within the catheter's connector/hub, such as within the
lumen/duct 254 and/or within a widened portion of the catheter's in
vivo portion.
[0638] FIG. 2H provides another exemplary embodiment of a
multi-sensor apparatus, namely a connector, such as a Leur lock, a
Y-connector, a T-connector, an X-connector, or a valve configured
for connecting IV equipment. The multi-sensor apparatus includes a
proximal orifice (e.g., with respect to the host) configured to
couple with a vascular access device (e.g., a catheter/cannula) or
with various IV equipment, such as IV tubing or another connector,
and a distal orifice (e.g., with respect to the host) configured to
fluidly couple to other IV equipment, as described herein and is
known to one skilled in the art. The analyte sensors 240 are
disposed within the multi-sensor apparatus's lumen or duct 254.
[0639] In various embodiments, the analyte sensors (of the
multi-sensor apparatus) can be configured to detect an analyte
using any means known in the art, such as but not limited to by
enzymatic, chemical, physical, electrochemical, spectrophotometric,
polarimetric, calorimetric, radiometric, or immunochemical
techniques, or by a combination of these techniques. Further more,
each sensor can use a different detection technique. For example, a
first analyte sensor can detect a first analyte using a first
technique, a second analyte sensor can detect a second analyte
using a second technique, a third analyte sensor can detect a third
analyte using a third technique, and so on. Additionally, in some
embodiments, a detection technique can be used by more than one of
the analyte sensors, wherein the technique is modified to detect a
particular analyte of interest by each of the sensors. For example,
a first sensor can be configured to detect glucose enzymatically,
and a second sensor can be configured to detect cholesterol
enzymatically. In some embodiments, one of the plurality of sensors
is configured to detect an analyte optically, as described
elsewhere herein. Additionally, in some embodiments, two or more of
the sensors are configured to detect the same analyte, either by
the same or different detection techniques.
[0640] FIGS. 2I through 2L are cross-sections of the multi-sensor
apparatus of FIGS. 2G and 2H taken along line 2I-2I, looking
towards the proximal ends (e.g., 212b/258) of the devices. A
plurality of analyte sensors 240 is located at the luminal surface
of wall 260 (e.g., the interior surface of the hub/connector). In
some embodiments, one or more of the plurality of sensors is
integrally formed with the multi-sensor apparatus. In some
embodiments, the multi-sensor apparatus includes a plurality of
sensor sites 262, wherein each sensor site 262 is configured to
receive a sensor. In some embodiments, at least one of the
plurality of sensor sites 262 comprises a breakaway portion (or a
plug) configured for insertion therethrough of a sensor, such that
at least a portion of the sensor is disposed within the lumen. One
or more of the breakaway portions can be removed, such a by
punching them out, to form a channel through the wall 260. In some
embodiments, the multi-sensor apparatus is manufactured such that
one or more of the sensor sites includes a channel (e.g., through
the wall), such that a sensor can be inserted there through. The
sensor(s) can be installed by insertion through the channel(s). An
adhesive, press-fit, clip or other attachment means can be use to
secure the sensor(s) in place. In some embodiments, a portion of a
sensor 240 (e.g., the sensing portion) inserted through the wall
260 is disposed at the surface of the duct/lumen. In some
embodiments, the portion of the sensor protrudes into the
duct/lumen 254. In some further embodiments, at least another
portion of the sensor is disposed at the external surface of the
connector/hub. In some embodiments, one or more sensors can be
disposed (e.g., installed) within the duct/lumen by adhering the
sensor at the surface of the duct/lumen. In some embodiments, one
or more of the sensors is deposited at the surface of the
duct/lumen using known analyte sensor deposition techniques. In
some embodiments, conductive traces, leads or wires can be
applied/installed, such that the sensor(s) can be connected to
device electronics, as is understood by one skilled in the art. For
example, the device shown in FIGS. 1A and 1B include a conductive
lead 24, for connecting the analyte sensor to electronics.
[0641] Referring again to FIG. 2G, in some embodiments, the
multi-sensor apparatus is a vascular access device comprising an in
vivo portion and an ex vivo portion. In some preferred embodiments,
the plurality of analyte sensors are disposed only within the ex
vivo portion of the device, and thus do not extend into the in vivo
portion (e.g., catheter 212). In this embodiment, the plurality of
sensors does not extend beyond a plain defined by the host's skin.
In some embodiments, the in vivo portion of the multi-sensor
apparatus includes a widened portion, such as a portion adjacent to
and/or near to the hub, and one or more of the plurality of sensors
are disposed within the widened portion. In some embodiments, one
or more of the analyte sensor can be configured to extend into the
in vivo portion, and in some embodiments to extend into the host's
circulatory system.
[0642] Referring again to FIG. 2H, in some embodiments, the
multi-sensor apparatus is a connector configured to be disposed
outside the host's body. Accordingly, the multi-sensor apparatus
does not include an in vivo portion. In this embodiment, the
multi-sensor apparatus is configured to fluidly couple to a
vascular access device at its proximal end and to a flow control
device at its distal end, such that the flow control device can
meter the flow of a non-bodily fluid (e.g., saline, a glucose
solution, etc.) through the device and into the host, as well as
withdrawal of blood samples from the host (e.g., such that the
sample(s) contact the analyte sensor(s)) and (optionally)
reinfusion of the blood samples to the host. The multi-sensor
apparatus of this embodiment includes a lumen and/or duct, in which
the plurality of analyte sensors is disposed. In some embodiments,
at least one of the plurality of analyte sensors is configured to
extend into the lumen of a fluidly coupled catheter; and in some
further embodiments to extend through the catheter and into the
host's circulatory system.
[0643] In preferred embodiments, at least one of the plurality of
sensors (of the multi-sensor apparatus) is configured to generate a
signal associated with a concentration of an analyte in a sample of
the host's circulatory system. More preferably, each of the analyte
sensors generates a signal associated with a concentration of each
sensor's respective analyte in the blood sample withdrawn from the
host. In some embodiments, the sensors can be configured to
generate signals associated with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or
more analytes and/or properties of the sample of the host's
circulatory system. In some embodiments, two or more of the sensors
are configured to detect the same analyte, such as to provide
system redundancy and/or fail-safes. The analyte sensors can be
configured to detect a wide variety of analytes, such as but not
limited to glucose, oxygen, CO.sub.2 (carbon dioxide, bicarbonate),
pH, creatinine, urea (nitrogen), bilirubin, electrolytes (e.g.,
sodium, potassium, chloride, phosphorous, magnesium), albumin,
total protein, liver enzymes (e.g., alkaline phosphatase, alanine
amino transferase, aspartate amino transferase), antibodies against
infective agents, fibrinogen, fibronectin, lipids, triglycerides,
cholesterol-protein complexes and ratios thereof (e.g., LDL, HDL,
chylomycrons), hormones (e.g., T3, T4, TSH, hGH, interleukins,
etc.), medicaments, metabolites, and the like. A more extensive
list of analytes can be found in the "Definitions" section. In some
embodiments, at least one of the plurality of sensors is configured
to generate a signal associated with a property of a sample of the
host's circulatory system. Blood properties include but are not
limited to pH, temperature, oxygen tension, hematocrit, viscosity,
clotting, pressure, and the like.
[0644] The multi-sensor apparatus of the preferred embodiments can
be manufactured using a variety of techniques known in the art. For
example, in some embodiments, the analyte sensors are integrally
formed with the multi-sensor apparatus. In some embodiments, at
least one of the pluralities of sensors is deposited within the
lumen of the multi-sensor apparatus, such as in the lumen/duct of
the connector of the hub of the device illustrated in FIG. 2G, or
in the lumen/duct of the device of FIG. 2H. In some embodiments,
one or more of the analyte sensors is configured to extend out of
the connector/hub. For example, in the exemplary embodiment
illustrated in FIG. 2G one or more analyte sensors 240 can be
configured to extend into and/or through the lumen 212a of the
catheter 212. In another example, in the exemplary embodiment
illustrated in FIG. 2H one or more analyte sensors 240 can be
configured to extend out of the proximal end of the multi-sensor
apparatus, such that the sensor(s) can be inserted into and/or
through a vascular access device.
[0645] In some embodiments, the non-sensor portion of a
multi-sensor apparatus is formed, and then the plurality of sensors
are applied/installed. In some embodiments, at least one of the
pluralities of sensors is deposited within the lumen, such as by
screen printing. In some embodiments, at least one of the
pluralities of sensors is applied to the interior surface of the
lumen, such as via an adhesive.
[0646] Alternatively, the multi-sensor apparatus may be formed
about the plurality of analyte sensors, such as by using injection
molding. For example, a mold is prepared, including sites for the
analyte sensors (e.g., these will be "sensor sites," as described
elsewhere herein, when the manufacture process is complete). Prior
to injection molding, the sensors (e.g., previously manufactured)
are placed in the sites. The mold is closed and a material, such as
but not limited to, e.g., molten plastic, is injected into the
mold. The material fills all of the spaces within the mold,
including flowing around portions of the analyte sensors, such that
when the mold is cooled, the analyte sensors will be held in place
by the wall of the multi-sensor apparatus. For example, one or more
of the sensors pass through the wall of the multi-sensor apparatus.
In another example, the sensor can be oriented such that when the
injection molding process is completed, the analyte sensor is
disposed on the surface of the lumen. In some embodiments, one or
more of the analyte sensors can be installed in the multi-sensor
apparatus during injection molding, followed by application of one
or more additional sensors to the lumen of the device.
Alternatively, the body of the multi-sensor apparatus, such as a
fluid coupler, can be formed as mating injection-molded
portions/pieces that mate together about sensors placed in sensor
receiving sites (e.g., see FIGS. 2O-2P). A detailed description of
this manufacturing process can be found in the section entitled
"Exemplary Sensor Configurations." In still other embodiments, the
multi-sensor apparatuses can be formed as shown in FIGS. 2Q-2S, as
described elsewhere herein, by inserting whole sensors in place of
individual electrodes, for example.
[0647] As a non-limiting example, a method for making a
multi-sensor apparatus for the detection of a plurality of analytes
in a circulatory system of a host in vivo is provided, in some
embodiments. In some embodiments, a plurality of sensors is first
provided. The sensors can be configured to detect one or more
analytes using a variety of detection means known to one skilled in
the art. Next, a multi-sensor apparatus is formed about the
plurality of sensors. The multi-sensor apparatus formed includes a
lumen, an external surface, and at least one orifice configured for
coupling with a fluid flow device, as described herein.
[0648] As another non-limiting example, in some embodiments, a
method for making a multi-sensor apparatus for the detection of a
plurality of analytes in a circulatory of a host in vivo includes
providing a multi-sensor apparatus comprising a lumen, an external
surface, and at least one orifice configured for coupling with a
fluid flow device a plurality of sensors; followed by forming a
plurality of sensor within and/or on the multi-sensor
apparatus.
[0649] As yet another non-limiting example, a method for detecting
of a plurality of analytes in a circulatory of a host in vivo,
using a multi-sensor apparatus of the preferred embodiments, is
provided. Accordingly, a multi-sensor apparatus of the preferred
embodiments is applied to the circulatory system of a host. As
described elsewhere herein, the multi-sensor apparatus includes a
lumen and a plurality of sensors, wherein the at least two sensor
are disposed above a plane defined by the skin of the host when the
multi-sensor apparatus is applied to the host's circulatory system.
For example, in some embodiments, the multi-sensor apparatus is a
catheter with sensors in the hub/connector, which is
inserted/implanted into a host's artery/vein. After the catheter
has been inserted/implanted into the host, at least two of the
sensors remain disposed outside the host's body, as defined by the
host's skin. As another example, in some embodiments, the
multi-sensor apparatus is a connector with sensors within its
lumen. In this embodiment, the multi-sensor apparatus must be
fluidly coupled to a vascular access device, so that blood can be
withdrawn from the host's artery/vein and then contact the sensors
within the connector. Thus, at least two of the sensors within this
embodiment of the multi-sensor apparatus remain disposed outside
the host's body, as defined by the host's skin.
[0650] Next, a sample (e.g., blood) is withdrawn from the host's
circulatory system. When the sample is withdrawn, it is then
contacted with the plurality of sensors. Each of the sensors then
generates a signal. As described elsewhere herein, each sensor is
configured to detect an analyte. Accordingly, the signal generated
by each sensor is associated with the analyte that sensor was
configured to detect. The sensors can be configured to generate the
signal using any method know in the art, such as but not limited to
electrochemically generating the signal, optically generating the
signal, radiochemically generating the signal, physically
generating the signal, chemically generating the signal,
immunochemically generating the signal, and/or enzymatically
generating a signal, or combinations thereof.
[0651] In some embodiments, a withdrawn sample is reinfused into
the host. For example, a flow control device can meter the flow of
an infusion fluid into the host, and the infusion fluid pushes the
withdrawn sample back into the host. In some embodiments, the
device is configured to dispose of the withdrawn sample, such as by
directing the sample to a waste container.
[0652] As described herein, in some embodiments, an infusion fluid
is metered through the multi-sensor apparatus, and infused into the
host. In some embodiments, the plurality of sensors is washed with
the infusion fluid. For example, infusion of about 0.5, 1, 5, 10,
15 ml or more of infusion fluid into the host can effectively wash
a previous blood sample off of the plurality of analyte sensor in
some embodiments. A variety of infusion fluids can be used,
including but not limited to saline, reference fluids, medicaments,
parenteral nutrition fluids, hydration fluid and the like.
[0653] In preferred embodiments, the signal of at least one of the
plurality of sensors can be calibrated. A variety of calibration
methods can be used. In some embodiments, one or more of the
analyte sensors can be calibrated using one or more reference data
points provided by a device separate from the multi-sensor
apparatus/system. For example, a hand-held glucose meter can be
used to provide one or more data points for calibrating a glucose
sensor disposed in the multi-sensor apparatus. In some embodiments,
a substantially stable and/or constant analyte found in the host's
blood can be used to calibrate one or more of the plurality of
analyte sensors. In some embodiments, data from a recently
disconnected multi-sensor apparatus can be used to calibrate one or
more of the sensors of a newly installed/applied multi-sensor
apparatus. In some embodiments, one of the pluralities of analyte
sensors can be used to calibrate one or more of the other sensors.
In some embodiments, one or more of the sensors can be calibrated
by the manufacturer. Additional methods of calibration that can be
used with the multi-sensor apparatus of the preferred embodiments
are described elsewhere herein.
[0654] Noise
[0655] Generally, implantable sensors measure a signal (e.g.,
counts) related to an analyte of interest in a host. For example,
an electrochemical sensor can measure glucose, creatinine, or urea
in a host, such as an animal, especially a human. Generally, the
signal is converted mathematically to a numeric value indicative of
analyte status, such as analyte concentration. However, it is not
unusual for a sensor to experience a certain level of noise. The
term "noise" generally refers to a signal detected by the sensor
that is substantially non-analyte related (e.g., non-glucose
related). In other words, things other than the analyte
concentration substantially cause noise. Noise is clinically
important because it can reduce sensor performance, such as by
making the analyte concentration appear higher or lower than the
actual concentration. For example, if a host is hyperglycemic
(e.g., blood sugar too high, greater than .about.120 mg/dl) or
euglycemic (e.g., .about.80-120 mg/dl), noise can cause the host's
blood sugar to appear higher than it truly is, which can lead to
improper treatment decisions, such as to give the host an excessive
insulin dose. An excessive insulin dose, in some circumstances, can
lead to a dangerous hypoglycemic state (e.g., blood sugar too low,
less than .about.80 mg/dl). In the case of a hypoglycemic host,
noise can cause the hosts blood sugar to appear euglycemic or even
hyperglycemic, which can also lead to improper treatment decisions,
such as not eating when necessary or taking insulin, for example.
Accordingly, since noise can cause error and reduce sensor
performance, noise reduction is desirable.
[0656] Noise is comprised of two components, constant noise and
non-constant noise, and can be caused by a variety of factors,
ranging from mechanical factors to biological factors. For example,
it is known that macro- or micro-motion, ischemia, pH changes,
temperature changes, pressure, stress, or even unknown mechanical,
electrical, and/or biochemical sources can cause noise. In general,
"constant noise" (sometimes referred to as constant background or
baseline) is caused by factors that are relatively stable over
time, including but not limited to electroactive species that arise
from generally constant (e.g., daily) metabolic processes. In
contrast, "non-constant noise" (sometimes referred to as
non-constant background) is caused by transient events, such as
during wound healing or in response to an illness, or due to
ingestion (e.g., some drugs). In particular, noise can be caused by
a variety of interfering species (constant or non-constant).
Interfering species can be compounds, such as drugs that have been
administered to the host, or products of various host metabolic
processes. Exemplary interferents include but are not limited to a
variety of drugs (e.g., acetaminophen), H.sub.2O.sub.2 from
exterior sources, reactive metabolic species (e.g., reactive oxygen
and nitrogen species, some hormones, etc.). In some circumstances,
constant noise-causing factors can have an affect on the sensor
signal similar to non-constant noise-causing factors, such as when
the concentration of a constant noise-causing factor temporarily
increases, such as due to temporary lack of lymph flow (see
discussion of intermittent sedentary noise).
[0657] 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).
[0658] Noise can be recognized and/or analyzed in a variety of
ways. 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. Patent Publication No.
US-2005-0043598-A1. Additional description can also be found in
U.S. Patent Publication No. US-2007-0032706-A1, both herein
incorporated by reference in their entirety.
[0659] Reduction of Noise
[0660] Noise can be recognized and substantially reduced and/or
eliminated by a variety of sensor configurations and/or methods,
such as by using 1) sensor configurations that block and/or remove
the interferent, or that specifically detect the noise and 2)
mathematical algorithms that recognize and/or remove the signal
noise component. The preferred embodiments provide devices and
methods for reducing and/or eliminating noise, such as by blocking
interferent passage to the sensor's electroactive surfaces,
diluting and/or removing interferents around the sensor and
mathematically determining and eliminating the noise signal
component. Those knowledgeable in the art will recognize that the
various sensor structures (e.g., multiple working electrodes,
membrane interference domains, etc.), bioactive agents, algorithms
and the like disclosed herein can be employed in a plurality of
combinations, depending upon the desired effect and the noise
reduction strategy selected. In preferred embodiments, the sensor
comprises at least two working electrodes (one with and one without
enzyme over its electroactive surface) and an interference domain
configured to substantially block interferent passage therethrough,
such that at least some interferent no longer has a substantial
affect on sensor measurements (e.g., at either working electrode).
The term "interference 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 any
mechanism of the membrane system configured to reduce any kind of
noise or interferants, such as constant and/or non-constant noise.
"Noise-reducing mechanisms" 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 any sensor
system component configuration that reduces and/or eliminates noise
on the sensor signal. Such structural configurations include but
are not limited to electrode configurations (e.g., two or more
working electrodes), membrane configurations (e.g., interference
domain), algorithmic configurations (e.g., signal processing to
remove an identified noise component of the signal), and the like.
In some embodiments, the interference domain is a component of the
membrane system, such as shown in FIG. 3C. However, the
interference domain can be disposed at any level (e.g., layer or
domain) of the membrane system (e.g., more proximal or more distal
to the electroactive surfaces than as shown in FIG. 3C). In some
other embodiments, the interference domain is combined with an
additional membrane domain, such as the resistance domain or the
enzyme domain.
[0661] In another aspect, the sensor is configured to reduce noise,
including non-constant non-analyte related noise with an
overlapping measuring potential with the analyte. A variety of
noise can occur when a sensor has been implanted in a host.
Generally, implantable sensors measure a signal (e.g., counts) that
generally comprises at least two components, the background signal
(e.g., background noise) and the analyte signal. The background
signal is composed substantially of signal contribution due to
factors other than glucose (e.g., interfering species,
non-reaction-related hydrogen peroxide, or other electroactive
species with an oxidation/reduction 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.
[0662] 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.
[0663] 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).
[0664] In contrast, "noise" as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a
substantially intermittent signal caused by relatively non-constant
factors (e.g., the presence of intermittent noise-causing compounds
that have an oxidation/reduction potential that substantially
overlaps the oxidation/reduction 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).
[0665] 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. Patent Publication No.
US-2005-0043598-A1 and U.S. Patent Publication No.
US-2007-0027370-A1, herein incorporated by reference in their
entirety.
[0666] 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.
[0667] 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.
[0668] In one embodiment, the sensor is configured to substantially
eliminate (e.g., subtract out) noise due to mechanical factors.
Mechanical factors include macro-motion of the sensor, micro-motion
of the sensor, pressure on the sensor, local tissue stress, and the
like. Since both working electrodes are constructed substantially
symmetrically and identically, and due to the sensor's small size,
the working electrodes are substantially equally affected by
mechanical factors impinging upon the sensor. For example, if a
build-up of noise-causing compounds occurs (e.g., due to the host
pressing upon and manipulating (e.g., fiddling with) the sensor,
for example) both working electrodes will measure the resulting
noise to substantially the same extend, while only one working
electrode (the first working electrode, for example) will also
measure signal due to the analyte concentration in the host's body.
The sensor then calculates the analyte signal (e.g., glucose-only
signal) by removing the noise that was measured by the second
working electrode from the total signal that was measured by the
first working electrode.
[0669] 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.
[0670] 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/reduction potential. For example, the oxidation/reduction
potential of the non-glucose related electroactive compounds
substantially overlaps with the oxidation/reduction potential of
H.sub.2O.sub.2, which is produced according to the reaction of
glucose with GOx and subsequently transfers electrons to the first
working electrode (e.g., E1; FIG. 3F). 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/reduction potential that substantially
overlaps with the oxidation/reduction potential of H.sub.2O.sub.2
(the co-analyte). The first and second working electrodes
integrally form at least a portion of the sensor, such as but not
limited to the in vivo portion of the sensor, as discussed
elsewhere herein. Furthermore, the sensor has a diffusion barrier
that substantially blocks (e.g., attenuates) diffusion of glucose
or H.sub.2O.sub.2 between the first and second working electrodes.
In various embodiments, the sensor includes a diffusion barrier
configured to be physical, spatial, and/or temporal.
[0671] FIG. 3F is a schematic illustrating one embodiment of a
sensor (e.g., a portion of the in vivo portion of the sensor, such
as but not limited to the sensor electroactive surfaces) having one
or more components that act as a diffusion barrier (e.g., prevent
diffusion of electroactive species from one electrode to another).
The first working electrode E1 is coated with an enzyme layer 348
comprising active enzyme. For example, in a glucose sensor, the
first working electrode E1 is coated with glucose oxidase enzyme
(GOx). A second working electrode E2 is separated from the first
working electrode E1 by a diffusion barrier D, such as but not
limited to a physical diffusion barrier (e.g., either a reference
electrode or a layer of non-conductive material/insulator). The
diffusion barrier can also be spatial or temporal, as discussed
elsewhere herein.
[0672] Glucose and oxygen diffuse into the enzyme layer 348, where
they react with GOx, to produce gluconate and H.sub.2O.sub.2. At
least a portion of the H.sub.2O.sub.2 diffuses to the first working
electrode E1, where it is electrochemically oxidized to oxygen and
transfers two electrons (e.g., 2e.sup.-) to the first working
electrode E1, which results in a glucose signal that is recorded by
the sensor electronics (not shown). The remaining H.sub.2O.sub.2
can diffuse to other locations in the enzyme layer or out of the
enzyme layer (illustrated by the wavy arrows). Without a diffusion
barrier D, a portion of the H.sub.2O.sub.2 can diffuse to the
second working electrode E2, which results in an aberrant signal
that can be recorded by the sensor electronics as a non-glucose
related signal (e.g., background).
[0673] Preferred embodiments provide for a substantial diffusion
barrier D between the first and second working electrodes (E1, E2)
such that the H.sub.2O.sub.2 cannot substantially diffuse from the
first working electrode E1 to the second working electrode E2.
Accordingly, the possibility of an aberrant signal produced by
H.sub.2O.sub.2 from the first working electrode E1 (at the second
working electrode E2) is reduced or avoided.
[0674] In some alternative embodiments, the sensor is provided with
a spatial diffusion barrier between electrodes (e.g., the working
electrodes). For example, a spatial diffusion barrier can be
created by separating the first and second working electrodes by a
distance that is too great for the H.sub.2O.sub.2 to substantially
diffuse between the working electrodes. In some embodiments, the
spatial diffusion barrier is about 0.01, 0.02, 0.03, 0.04, 0.05,
0.06, 0.07, or 0.08 inches to about 0.09, 0.10, 0.11, or 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
(e.g., a polymer structure or coating such as Parylene) can be
configured to act as a spatial diffusion barrier.
[0675] In some preferred 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 in U.S. Patent Publication No.
US-2008-0083617-A1 which is incorporated by reference herein in its
entirety.
[0676] In one exemplary embodiment of an indwelling analyte sensor,
such as but not limited to an intravascular glucose sensor to be
used from a few hours to ten days or longer. Namely, the sensor
includes two working electrodes. A first working electrode detects
the glucose-related signal (due to active GOx applied to the
electroactive surface) as well as non-glucose related signal. The
second working electrode detects only the non-glucose related
signal (because no active GOx is applied to its electroactive
surface). H.sub.2O.sub.2 is produced on the first working electrode
(with active GOx). If the H.sub.2O.sub.2 diffuses to the second
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 Publication No. US-2008-0119703-A1, herein
incorporated in its entirety by reference.
[0677] 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 in the host's blood flow (e.g., in an artery or
vein), active GOx and the inactive GOX (or no GOx) would be applied
to two working electrodes such that the active GOX would be
downstream from the inactive GOX (e.g., relative to the direction
of blood flow). Due to this configuration, H.sub.2O.sub.2 produced
at plus-GOX electroactive surface would be carrier down stream
(e.g., away from minus-GOX electroactive surface) and thus not
affect the non-enzymatic working electrode.
[0678] In some embodiments, a physical diffusion barrier is
provided by a physical structure, such as an electrode, insulator,
and/or membrane. For example, in some embodiments, an insulator or
reference electrode disposed between the working electrodes acts as
a diffusion barrier. As another example, the diffusion barrier can
be a bioprotective membrane (e.g., a membrane that substantially
resists, attenuates or blocks the transport of a species (e.g.,
hydrogen peroxide), such as a polyurethane. 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.
[0679] In other embodiments, a temporal diffusion barrier is
provided (e.g., between the working electrodes). By temporal
diffusion barrier is meant a period of time that substantially
prevents an electroactive species (e.g., H.sub.2O.sub.2) from
diffusing from a first working electrode to a second working
electrode. For example, in some embodiments, the differential
measurement can be obtained by switching the bias potential of each
electrode between the measurement potential and a non-measurement
potential. The bias potentials can be held at each respective
setting (e.g., high and low bias settings) for as short as
milliseconds to as long as minutes or hours. Pulsed amperometric
detection (PED) is one method for 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.
[0680] 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 (e.g.,
attenuate, restrict, suppress) diffusion of glucose or hydrogen
peroxide between the first and second working electrodes.
[0681] In a further embodiment, the glucose sensor includes a
reference electrode configured integrally with the first and second
working electrodes. In some embodiments, the reference electrode
can be located remotely from the sensor, as described elsewhere
herein. In some embodiments, the surface area of the reference
electrode is at least six times the surface area of the working
electrodes. In some embodiments, the sensor includes a counter
electrode that is integral to the sensor or is located remote from
the sensor, as described elsewhere herein.
[0682] In a further embodiment, the glucose sensor detects a first
signal associated with glucose and non-glucose related
electroactive compounds having a first oxidation/reduction
potential (e.g., the oxidation/reduction potential of
H.sub.2O.sub.2). In some embodiments, the glucose sensor also
detects a second signal is associated with background noise of the
glucose sensor comprising signal contribution due to interfering
species, non-reaction-related hydrogen peroxide, or other
electroactive species with an oxidation/reduction potential that
substantially overlaps with the oxidation/reduction 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
[0683] 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.
[0684] Sensor Configurations for Equivalent Measurement of Noise
Signals at the Two Working Electrodes
[0685] In dual-electrode biosensors (e.g., an analyte sensor having
two working electrodes E1, E2), noise can be caused by a variety of
sources, for example, located outside (e.g., by noise-causing
species produced metabolically and/or consumed by the host) or
within (e.g., crosstalk) the sensor. In some circumstances,
biological and/or metabolic processes occurring in the host's body,
such as in the locale of the implanted sensor, can cause noise.
These metabolic processes, such as but not limited to wound
healing, the body's response to illness and even daily cellular
metabolic processes, can generate noise-causing metabolic species
(e.g., compounds, substances) that impinge upon the sensor and
cause noise on the signal. For example, some noise-causing species,
the levels of which are relatively stable due to production during
daily cellular metabolism, generally cause constant noise. In
another example, some noise-causing species, the levels of which
fluctuate due to production by intermittent metabolic process
(e.g., wound healing or response to infection), generally cause
non-constant noise. Noise-causing metabolic species include but are
not limited to externally generated H.sub.2O.sub.2 (e.g., produced
outside the sensor), compounds having 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,
reactive oxygen species or other electroactive species or
metabolites produced during cell metabolism and/or wound healing,
for example. Noise-causing species, such as drugs, vitamins and the
like, can also be consumed by the host. These noise causing species
include but are not limited to acetaminophen, ascorbic acid,
dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate,
tetracycline, tolazamide, tolbutamide and triglycerides. Further
discussion of noise and its sources can be found in U.S. Patent
Publication No. US-2007-0027370-A1 and U.S. Patent Publication No.
US-2007-0235331-A1, both of which are incorporated herein by
reference in their entirety.
[0686] In dual-electrode sensors, noise can also be generated
within the sensor, namely due to diffusion of a measured species
(e.g., H.sub.2O.sub.2) from a first working electrode (e.g., the
H.sub.2O.sub.2 is generated in an active enzymatic portion of the
sensor membrane associated with the first working electrode) to a
second working electrode and detection thereby (e.g., which is
associated with a non-enzymatic portion of the sensor membrane).
This type of noise is commonly referred to as "crosstalk."
Crosstalk is undesirable as it causes sensor error, which can
result in inaccurate reporting of sensor data. In conventional
sensors, a common solution to the problem of crosstalk is to space
the two working electrodes far enough apart that a measured species
diffusing from one working electrode cannot reach the other working
electrode; unfortunately, such spacing does not enable
substantially equivalent measurement of noise-cause species, as
discussed in more detail elsewhere herein. Unlike conventional
sensors, the sensors of the preferred embodiments ensure accurate
subtraction of noise signal by ensuring substantially equivalent
measurement of the noise (e.g., noise component, constant and/or
non-constant noise components) detected by the two working
electrodes.
[0687] Depending upon the scale (e.g., point) of reference, noise
has a dual nature. On a larger scale, with respect to the in vivo
portion of the sensor and the surrounding tissue, noise occurs
randomly (e.g., is scattered, intermittent, dispersed, unevenly
distributed) in the local of an implanted sensor. Yet, on a smaller
scale, such as that of a few cells (e.g., 100-300 microns), noise
is a localized phenomenon because it creates hot spots of
noise-causing species generation whose effects extend about a
thousandths of an inch (e.g., localized nature, character). A "hot
spot" of noise generation is referred to herein as a "point
source." A point source (e.g., a localized hot spot for noise
generation) can be a cell or a group of cells adjacent to the
sensor membrane, or a noise-causing species (e.g., compound,
substance, molecule) that diffused to the location of sensor
implantation, such as by diffusion between cells (e.g., to the
sensor). For example, in the circumstance of a single point source
in contact with the sensor membrane's surface, noise is a local
phenomenon, because the noise-causing species' ability to affect
adjacent structures is limited by the maximum distance it can
diffuse (e.g., through the membrane), which is generally very short
(e.g., a few microns, such as between about 1-.mu.m to about
500-.mu.m). Due to the random yet localized nature of noise, the
configuration of the electroactive surfaces (of the working
electrodes) can substantially affect noise measurement. With
respect to the configuration and arrangement (e.g., surface area)
of the dual-electrode sensor's electroactive surfaces, the random
yet localized nature of noise is discussed in greater detail
below.
[0688] FIG. 3G is a two-dimensional schematic illustrating, on the
scale of a sensor and the surrounding tissue (e.g., a generally
larger scale), the random nature of noise relative to a
dual-electrode sensor, in one exemplary embodiment. This figure is
for illustrative purposes only, and should not be considered as a
to-scale representation of a particular sensor configuration or of
the events discussed herein. In the embodiment shown in FIG. 3G,
the dual-electrode analyte sensor includes two electroactive
surfaces E1, E2 disposed beneath the sensor's membrane. While FIG.
3G illustrates only one dimension of the electroactive surfaces, in
some embodiments, the electroactive surfaces (e.g., the surface
area of each electroactive surface) can include both a length and a
width. In some embodiments, the area can include additional
dimensions, such as a circumference and/or a height. In some
embodiments, the sensor can have a planar configuration. In some
embodiments, the sensor can have a cylindrical, pyramidal,
polygonal configuration. It should also be understood that the
electroactive surfaces E1, E2 are shown as boxes as a matter of
illustrative convenience; however, electroactive surfaces can be
thinner or thicker than illustrated in FIG. 3G or elsewhere herein.
The membrane has a thickness D1 and a surface MS. Depending upon
the membrane configuration, fabrication methods and/or materials,
D1 can vary in size, from less than about 0.001, 0.002, 0.003,
0.004, 0.005, 0.006, 0.007, 0.008, 0.009, or 0.010 inches to more
than about 0.011, 0.012, 0.013, 0.014, 0.015, 0.015, 0.016, 0.017,
0.018, 0.019, 0.020, 0.025, 0.03, 0.035, or 0.050 inches. In some
embodiments, a preferred membrane thickness is between about 0.001,
0.0012, 0.0014, 0.0016, or 0.0018 inches to about 0.002, 0.0022,
0.0024, 0.0026, 0.0028, or 0.003 inches. Noise-causing species
(represented by squiggly arrows N2) can be generated by and/or at
point sources N1 (e.g., noise hot spots) unevenly distributed
relative the in vivo portion of the sensor. For example, some of
the point sources N1 (shown in FIG. 3G) are concentrated at one end
of electroactive surface E1, while some are distributed more evenly
across electroactive surface E2. In some circumstances, the point
source may be one or more cells (e.g., in contact with the membrane
surface MS) that release the noise-causing species during wound
healing or another metabolic process, such as when a sensor is
implanted in vivo. In some circumstances, the implanted sensor can
be located within the diffusion distance of one or more
noise-causing species produced during a nearby metabolic process.
In some circumstances, the noise-causing species (e.g., a compound
consumed by the host) can be carried to the local of the sensor via
the circulatory and/or lymph system and diffuse to the sensor
(e.g., between cells).
[0689] Random and/or unequally distributed noise can be generated
in a variety of circumstances. For example, a peroxide-generating
immune cell could be located adjacent to one electroactive surface
but not the other. In general, a noise-causing species must be
generated and/or occur close enough to the sensor membrane such
that it can diffuse to (and through) the membrane, to the
electroactive surfaces, and affect the sensor signal. If the
noise-causing species is generated farther away from the membrane
than the diffusion distance of the noise-causing species, then the
noise-causing species may be unable to reach the electroactive
surfaces, and therefore may have little effect on sensor signal.
For example, H.sub.2O.sub.2 (produced by metabolic process when the
sensor is implanted in a host) must be generated sufficiently close
to the membrane for it to diffuse to the membrane and affect sensor
function. The maximum distance that the noise-causing species can
diffuse (e.g., from the cell to the membrane, from one working
electrode to another working electrode) and still substantially
affect sensor function is referred to herein as a "diffusion
distance."
[0690] The sensor electronics are configured to mathematically
correct for noise on the sensor signal (e.g., such as by
subtraction of the noise signal, applying a filter, averaging, or
other calculations), such that a substantially analyte-only signal
can be presented to the user. The inventors have discovered that
successful mathematical correction of noise on the sensor signal
can be substantially affected by the equivalence (e.g., similarity)
of the noise signals detected by the two working electrodes. If the
detected noise signals are substantially equivalent (e.g., similar
amounts, amplitudes, levels, relatively equal), then the
calculations will produce a more accurate resultant analyte signal.
If, on the other hand, the detected noise signals are not
substantially equal (e.g., have very different amplitudes and/or
wave forms), then the calculations will have a greater degree of
error. While not wishing to be bound by theory, it is believed that
presentation of more accurate sensor data (e.g., to the host) will
improve the host's management of his or her diabetes, which will
prevent the immediate risks of hypoglycemia (e.g., loss of
consciousness and death) and postpone and/or prevent long term
diabetes complications (blindness, loss of limb, kidney
dysfunction, and the like). Additionally, the increased accuracy
afforded by the sensors of the preferred embodiment increases the
feasibility of insulin dosing and/or an artificial pancreas system
based on a continuous glucose sensor.
[0691] In order to compensate for the unevenly distributed nature
of noise (e.g., the point sources are randomly and/or non-equally
and/or non-equivalently distributed relative to the in vivo portion
of the sensor) and thereby render the noise components equivalent,
a continuous dual-electrode glucose sensor having sufficiently
large electroactive surfaces, such that the noise components can be
substantially equalized (e.g., made and/or become equivalent) by
integration there across, is provided in one embodiment. The first
working electrode includes a first electroactive surface (E1, FIG.
3G) disposed beneath an active enzymatic portion (e.g., plus-GOx)
of the sensor's membrane, as described elsewhere herein. The first
electroactive surface includes a first area (e.g., first
electroactive surface area) configured to detect a first signal
(e.g., including an analyte-related component and a noise
component) having a first noise component related to a
noise-causing species. The sensor also includes a second working
electrode having a second electroactive surface (E2, FIG. 3G)
disposed beneath an inactive-enzymatic or a non-enzymatic portion
of the sensor membrane, as described elsewhere herein. For example,
an inactive-enzymatic portion of the membrane can include
inactivated GOx or no GOx. The second electroactive surface
includes a second area (e.g., second electroactive surface area)
configured to generate a second signal having a second noise
component related to the noise-causing species. In preferred
embodiments, the first and second areas are dimensioned (e.g.,
sized) to be sufficiently large such that the first and second
noise components integrated there across, such that the first and
second integrated noise signals (e.g., from the first and second
electroactive surfaces, respectively) are substantially equivalent.
In some embodiments, the first and second integrated noise signals
(e.g., noise components) are within 20% of each other (e.g., plus
or minus 10%). In some embodiments, the first and second
electroactive surfaces are dimensioned to integrate noise caused by
a plurality of local point sources that produce noise-causing
species in vivo.
[0692] FIG. 3H is a two-dimensional schematic illustrating the
localized character of noise species (represented by squiggly
arrows N2) generated by a point source N1, when examined from a
cellular scale, as discussed elsewhere herein. FIG. 3H depicts a
cross-section of a sensor, in one embodiment, wherein the sensor
includes two working electrodes having electroactive surfaces E1
and E2, and a membrane having surface MS and thickness D1. Distance
D3 separates the electroactive surfaces; the distance between their
outer edges is denoted by D4. Note that dimension D2, described
above, is not shown in this figure. The sensor of this exemplary
embodiment can have a variety of configurations, such as but not
limited to planar, cylindrical or polygonal. Accordingly, the
dimensions of an electroactive surface's surface area (referred to
as "area" herein) can include but are not limited to length, width,
height, and/or circumference. For example, in some embodiments, the
area of each electroactive surface is defined by a length and a
width. In some embodiments, the area includes a length or width and
a circumference. In some embodiments, the area includes length,
width and height. Additionally, it is known to one skilled in the
art that, in some circumstances, differences in signal amplitude
and/or sensitivity (e.g., from the two working electrodes), due to
differences in electrode sizes (or some differences in compositions
of membranes) can be corrected (adjusted, compensated for,
calibrated out) mathematically. For example, if a first
electroactive surface is two times as large as the second
electroactive surface, then the signal from the second
electroactive surface can be multiplied by two, such that the
sensitivities are substantially similar.
[0693] Referring now to FIG. 3H, in this exemplary circumstance the
point source (e.g., noise hot spot) is an individual cell N1
disposed adjacent to the membrane surface MS and generally above
and/or over the sensor's electroactive surfaces E1, E2. The cell
can produce noise-causing substances (e.g., N2) that can diffuse to
and affect its local environment. In general, the ability of a
noise-causing substance to affect the local environment is limited
by the maximum distance the substance can diffuse (e.g., the
substance's diffusion distance). In some circumstances, some of the
noise-causing substances can diffuse through the sensor membrane
and affect the sensor's electroactive surfaces. While not wishing
to be bound by theory, the inventors have found that in order for
the two electroactive surfaces to be substantially equivalently
affected by the noise N2 from a point source, such as a cell, the
electroactive surfaces must be affected by substantially the same
microenvironment. In various circumstances, the electroactive
surfaces will be affected by substantially the same
microenvironment, if the electroactive surfaces are configured and
arranged such that the electroactive surfaces are sufficiently
close together and/or their external edges are sufficiently close
together.
[0694] FIG. 3H shows that the sensor's electroactive surfaces E1,
E2 are separated by a distance D3 and their outer edges are spaced
a distance D4 (e.g., in at least one dimension), in one exemplary
embodiment. In this example, a point source N1 (e.g., a cell) of
noise-causing species 1006 is adjacent to the membrane's surface
MS. If the electroactive surfaces are configured and arranged such
that D3 is sufficiently small, then the noise-causing species
diffusing from the point source can impinge equivalently on both of
the electroactive surfaces. Additionally or alternatively, if D4 is
sufficiently small (e.g., the electroactive surfaces are
sufficiently narrow in at least one dimension), then the
noise-causing species diffusing from the point source can impinge
equivalently on both of the electroactive surfaces. Accordingly, in
preferred embodiments, the electroactive surfaces are spaced a
distance (e.g., relative to each other, D3) such that the
electroactive surfaces (e.g., at least a portion of each
electroactive surface) detect substantially equivalent noise from a
point source. In some embodiments, the electroactive surfaces are
sufficiently close together (e.g., such that the noise components
measured are substantially equal) when the distance between the
electroactive surfaces (D3) is between about 0.5-times to about
10-times (or more) the membrane thickness (D1). In some preferred
embodiments, the electroactive surfaces are sufficiently close
together when D3 is about 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-times
the membrane thickness. In some embodiments, D3 is between about 5,
10, 15, 20, 25, 30, 35, 40, 45, or 50 microns or less to about 55,
60, 65, 70, 75, 80, 85, 90, 95, or 100 microns or more. In
preferred embodiments, D3 is between about 20 to about 40 microns.
In some embodiments, D4 is between about 25 microns or less to
about 500 microns or more.
[0695] Depending upon the sensor's configuration, in some
embodiments, D4 can be the distance between the outer edges of the
electroactive surfaces, or D4 can be a distance equivalent to the
maximum diameter of the bundles and/or twisted pair of working
electrodes. For example, FIG. 3H illustrates a cross-section of a
sensor (e.g., width and height), but doesn't illustrate any
additional dimensions (e.g., length). The cross-section could be
that of a planar sensor configuration, wherein the sensor also
includes an additional dimension that has not been shown, such as
but not limited to D2. In some circumstances, the sensor can have a
non-planar configuration. For example, in the embodiment shown in
FIG. 3I, the working electrodes E1, E2 are fabricated from two
wires. Since the wires are cylindrical, the electroactive surfaces
do not include outer edges. In this exemplary circumstance, D4 is
the total diameter of the bundled and/or twisted pair of working
electrodes. In both types of sensor configurations (e.g., planar
and non-planar), if D4 is sufficiently small, then the two working
electrodes can be equivalently affected by noise-causing species N2
derived from a point source N1.
[0696] As described above, dual-electrode sensors can be affected
by internally generated noise (e.g., generated by the sensor). The
inventors have found that, in general, when D3 is sized to be
sufficiently small such that the electroactive surfaces are
equivalently affect by noise from an adjacent point source, the
electroactive surfaces are also close enough together that
crosstalk (an internally generated noise) can occur. In general,
crosstalk is detection of an analyte signal generated at the
plus-GOx working electrode (wherein the electrode includes the
membrane portion thereon) by the minus-GOx working electrode
(including the No GOx membrane portion thereon). For example, when
the measured species is H.sub.2O.sub.2, crosstalk occurs when the
H.sub.2O.sub.2 diffuses from the plus-GOx enzyme domain to the No
GOx working electrode and is detected (e.g., a signal is generated
on the No GOx electrode). In general, crosstalk is undesirable as
it causes sensor error. However, in order for the two working
electrodes to measure equivalent noise signals from a point source
N1, the electroactive surfaces must be spaced very close together.
Accordingly, in preferred embodiments, this distance (D3) is less
than a crosstalk diffusion distance of the measured species. In
other words, D3 is shorter than the diffusion distance of
H.sub.2O.sub.2 (e.g., the maximum distance H.sub.2O.sub.2 can
diffuse from a first electrode to a second and still cause a signal
on the second electrode).
[0697] In conventional dual-electrode sensors, spacing the
electroactive surfaces within the crosstalk diffusion distance of
the measured species is generally undesirable due to increased
sensor error. However, in preferred embodiments, the sensor
includes a physical diffusion barrier configured to attenuate
crosstalk by physically blocking (e.g., suppressing, blocking,
restricting) some of the crosstalk from the active enzymatic
portion of the sensor membrane to the second electroactive surface.
More preferably, the physical diffusion barrier is configured and
arranged to attenuate and/or physically block a substantial amount
of the measurable species (e.g., H.sub.2O.sub.2) diffusing from the
active enzymatic portion of the membrane to the second
electroactive surface, such that there is substantially no signal
associated with crosstalk measured at the second working
electrode.
[0698] FIG. 3I is a schematic illustrating a perspective view of a
cross-section of a dual-electrode sensor that includes a physical
diffusion barrier D, in one exemplary embodiment. In this
embodiment, wires form the working electrodes E1, E2. The working
electrodes each include a membrane, including an electrode domain
347, an enzyme domain 248 and a resistance domain 249. For example,
E1 includes a first electrode domain, a first enzyme domain (Plus
GOx) and a first resistance domain, and E2 includes a second
electrode domain, a second enzyme domain (No GOx) and a second
resistance domain. In this particular exemplary embodiment, the
electrodes are placed together and coated with an additional
resistance domain 249A (e.g., a third resistance domain). Depending
upon the circumstances, the electrodes can be placed and/or held
together using a variety of methods, such as bundling, twisting,
wrapping, and the like, either alone or in combination. The
distances shown are as follows; a thickness of the membrane D1, at
least one dimension of the electroactive surface D2, a distance
between the electroactive surfaces D3, and a distance between the
outer edges of the electroactive surfaces D4. In the illustrated
exemplary embodiment, the first and second electroactive surfaces
extend about the circumferences of E1 and E2 (or portions thereof),
respectively.
[0699] In preferred embodiments, the physical diffusion barrier D
is disposed between the electroactive surfaces of working
electrodes E1 and E2. In some embodiments, the physical diffusion
barrier is formed of one or more membrane materials, such as those
used in formation of an interference domain and/or a resistance
domain. Such materials include but are not limited to silicones,
polyurethanes, cellulose derivatives (cellulose butyrates and
cellulose acetates, and the like) and combinations thereof, as
described elsewhere herein. In some embodiments, the physical
diffusion barrier includes one or more membrane domains. For
example, in the exemplary embodiment of FIG. 3I, the physical
diffusion barrier is a discontinuous portion of the membrane (e.g.,
separate, distinct or discontinuous membrane structures) disposed
between the first and second electroactive surfaces, and can
include one or more membrane portion(s) within distance D3 (e.g.,
interference and/or resistance domains). For example, in some
embodiments, H.sub.2O.sub.2 diffusing from the Plus GOX working
electrode to the No GOx working electrode must pass through two
"sensor membranes" such as the first and second resistance domains
disposed on E1 and E2 respectively, and optionally electrode,
interference and/or enzyme domains disposed on E2. In some
embodiments, the physical diffusion barrier includes first and
second barrier layers formed independently on the first and second
electrodes. In some embodiments the barrier layer is the resistance
domain 349. In still other embodiments, the physical diffusion
barrier can be a continuous membrane (and/or membrane domain(s))
disposed between the electroactive surfaces. In some embodiments,
the physical diffusion barrier attenuates (e.g., suppresses,
blocks, prevents) diffusion of the H.sub.2O.sub.2 (e.g., crosstalk)
by at least 2-fold. In preferred embodiments, crosstalk is
attenuated at least 5-fold. In a more preferred embodiment,
crosstalk is attenuated at least 10-fold. In some embodiments, the
physical diffusion barrier attenuates crosstalk at least about 50%.
In a further embodiment, the physical diffusion barrier is
configured and arranged to physically block an amount of the
measured species diffusing from the active enzymatic portion of the
membrane to the second electroactive surface, such that there is
substantially no signal associated with crosstalk measured at the
second working electrode.
[0700] In some embodiments, a dual-electrode sensor having a
physical barrier layer can be fabricated by initially preparing
(e.g., fabricating, building) the first and second working
electrodes E1, E2 independently (e.g., separately from each other),
followed by joining and/or grouping and/or bundling the working
electrodes and optionally applying one or more additional membrane
domains fabrication. In this exemplary embodiment, to the first
working electrode E1, an optional electrode domain 347, an enzyme
domain 348 (e.g., plus-GOx), and at least one layer of the
resistance domain material 349 (e.g., first resistance domain) are
sequentially applied. Similarly, to the second working electrode
E2, an optional electrode domain 347, an enzyme domain 348 (e.g.,
no-GOx), and at least one layer of the resistance domain material
349 (e.g., second resistance domain) are sequentially applied. The
working electrodes are then held together, such as but not limited
to by bundling and/or twisting them together, wrapping a material
around them, or by any other method known in the art. In this
embodiment, the physical diffusion barrier D includes a
discontinuous portion of a membrane (e.g., the initial layers of
the resistance domain material applied independently to the two
working electrodes) disposed between the first and second
electroactive surfaces.
[0701] In an alternative exemplary sensor embodiment, the sensor
includes working electrodes (including electroactive surfaces)
disposed on a planar substrate and/or surface. The electroactive
surfaces can be spaced a distance D3 that is sufficiently close
together that the electroactive surfaces are equivalently affected
by an adjacent noise hot spot (e.g., point source). In this
configuration, D3 is also sufficiently small that crosstalk can
occur between the Plus GOx working electrode (wherein the term
"electrode" includes the membrane disposed thereon, for the
purposes of this example) and the No GOx working electrode.
However, in preferred embodiments, crosstalk is substantially
attenuated by a physical diffusion barrier disposed between the
working electrodes. Namely, the electrode domains (if present) and
enzyme domains can be separately applied to the working electrodes
and/or electroactive surfaces; followed by application of a
continuous resistance domain applied thereon, such that a portion
the resistance domain is deposited between the working electrodes.
For example, a portion of resistance domain deposited on a planar
substrate and between working electrodes can attenuate diffusion of
the measured species (e.g., H.sub.2O.sub.2) from E1 to E2, such
that the noise measured on E1 and E2 is equivalent.
[0702] In the context of glucose sensors, one skilled in the art
recognizes that equivalent noise signals can have different
amplitudes, but equivalent signal patterns (e.g., rises, falls,
trends and the like) such that a noise component can be subtracted
out (as described elsewhere herein) while compensating for any
difference in signal amplitude (e.g., sensitivity of the first and
second working electrodes), as described elsewhere herein. In some
circumstances, the membrane portions associated with the working
electrodes (e.g., of a dual-electrode sensor) can possess different
sensitivities (e.g., signal sensitivities), such that the
amplitudes of the noise components measured by the working
electrodes are not equivalent. In some circumstances, the areas of
the electroactive surfaces may be different sizes, which can also
result in non-equivalent signal amplitudes, differences in measured
baselines and/or sensitivities between the first and second working
electrodes. While such differences in signal baseline and/or
sensitivity can be corrected mathematically (e.g., by mathematical
filters), mathematical correction of noise, in general, is improved
when the signal sensitivities of the first and second working
electrodes are closer. Accordingly, in a preferred embodiment, an
additional resistance domain 349A (e.g., applied continuously over
the discontinuous resistance domains 349 described elsewhere
herein) is provided, such that the signal sensitivities are
equivalent. In the exemplary embodiment shown in FIG. 3I, the
signal sensitivities are substantially equalized on a sensor
including the combination of discontinuous resistance domains
(e.g., resistance domains 349, applied independently to E1 and E2)
and a continuous resistance domain 349A (e.g., applied over and/or
adjacent to the discontinuous resistance domains). In other words,
the noise signals detected on both E1 and E2 will have
substantially the same amplitude (e.g., intensity, amount), as
described with reference to Example 7, below. In a preferred
embodiment, the sensitivities (of the working electrodes) are
within 40% of each other (e.g., plus or minus 20%). In a preferred
embodiment, the sensitivities (of the working electrodes) are
within 20% of each other (e.g., plus or minus 10%). In a more
preferred embodiment, the sensitivities (of the working electrodes)
are within 10% of each other (e.g., plus or minus 5%).
[0703] In an alternative embodiment, the sensor electrodes can be
disposed on a planar, cylindrical, pyramidal or otherwise shaped
support. For example, the sensor's first and second working
electrodes can be conductive traces deposited, such as by screen
printing, sputtering or other thin film techniques known in the
art, on a planar substrate. In this alternative embodiment, a
physical diffusion barrier can be formed by layers of resistance
domain material deposited separately (e.g., discontinuously) on
each working electrode and/or between the electrodes, for
example.
[0704] In the exemplary embodiments described above, diffusion of
the H.sub.2O.sub.2 from the first working electrode E1 to the
electroactive surface of the second working electrode E2 is first
attenuated by the resistance domain 349 disposed over the first
working electrode E1 (an independently formed first barrier layer),
and then again by the resistance domain 349 disposed over the
second working electrode E2 (an independently formed second barrier
layer), such that only insubstantial amounts of H.sub.2O.sub.2 can
reach the electroactive surface of the second working electrode. In
preferred embodiments, the first and second resistance domains are
configured and arranged to reduce diffusion of the measurable
species (e.g., H.sub.2O.sub.2) from the first electroactive surface
to the second electroactive surface by at least 2-fold. In more
preferred embodiments, the physical diffusion barrier is configured
and arranged to reduce diffusion of the measurable species by at
least 10-fold. In some embodiments, the physical diffusion barrier
is configured and arranged to reduce diffusion of the measurable
species by at least 3-, 4-, 5-, 6-, 7-, 8-, or 9-fold. In some
embodiments, the physical diffusion barrier is configured and
arranged to reduce diffusion of the measurable species by at least
20-, 30-, 40- or 50-fold, or more. In some embodiments, the
sensor's working electrodes E1, E2 are by an insulator, which
insulates the working electrodes from each other. In some
embodiments, the insulator is at least a portion of the sensor
membrane.
[0705] In some embodiments, a continuous glucose sensor configured
for insertion into a host and detecting glucose in the host is
provided. In general, the sensor includes first and second working
electrodes, wherein each working electrode includes an
electroactive surface (each including an area) disposed beneath a
sensor membrane. The first electroactive surface (e.g., of the
first working electrode) is disposed beneath an active enzymatic
portion (plus-GOx) of the membrane while the second electroactive
surface (of the second working electrode) is disposed beneath a
non-enzymatic (no-GOx) portion of the membrane. The non-enzymatic
portion of the membrane can include inactivated enzyme and/or no
enzyme. Additionally, each working electrode is configured to
generate a signal having a noise component related to a
noise-causing species. In some circumstances, the noise-causing
species is non-constant and related to a biological process.
Preferably, the first and second areas are sufficiently large such
that the noise components (e.g., first and second noise components
detected by the first and second working electrodes) are
substantially equivalent. In some embodiments, the first and second
areas are each greater than the sum of the diameters of about 10
average human cells, in at least one dimension. In some
embodiments, the first and second areas are each greater than about
500 .mu.m, in at least one dimension. Preferably, the first and
second areas (e.g., of the electroactive surfaces) are configured
and arranged such that the signals caused by a plurality of local
point sources (that produce noise-causing species when implanted in
a host) can be integrated along each area (e.g., each area
independently from the other). In some further embodiments, the
first and second areas are configured and arranged to integrate
signals detected about a circumference of the sensor. Preferably,
the first and second electroactive surfaces are spaced a distance
that is less than a crosstalk diffusion distance of a measured
species, such as H.sub.2O.sub.2 produced in the active enzymatic
portion of the membrane. In some embodiments, the sensor includes a
physical diffusion barrier configured and arranged to physically
block some crosstalk from the active enzymatic portion of the
membrane to the second electroactive surface. In some further
embodiments, the physical diffusion barrier is configured and
arranged to physically block a substantial amount of the measurable
species diffusing from the active enzymatic portion of the membrane
to the second electroactive surface (e.g., crosstalk), such that
there is substantially no signal associated with crosstalk measured
at the second working electrode. In some embodiments, the physical
diffusion barrier is a discontinuous portion of the membrane
disposed between the first and second electroactive surfaces. In
some further embodiments, the physical diffusion barrier includes a
first barrier layer formed on the first working electrode and a
second barrier layer formed on the second working electrode,
wherein the first and second barrier layers are independently
formed (e.g., formed separately on the two electroactive surfaces).
In some further embodiments, the physical diffusion barrier
includes a first resistance domain formed on the first working
electrode and a second resistance domain formed on the second
working electrode, and wherein the first and second resistance
domains are configured and arranged to reduce diffusion of the
measurable species (e.g., crosstalk) from the active enzymatic
portion of the sensor to the second electroactive surface by at
least 2-fold. In a preferred embodiment, the physical diffusion
barrier can reduce the diffusion of the measurable species (e.g.,
crosstalk) by at least 10-fold.
[0706] In some embodiments, the continuous glucose sensor includes
first and second working electrodes, each working electrode
including an electroactive surface (each including an area)
disposed beneath a sensor membrane. As described elsewhere herein,
the first electroactive surface is disposed beneath an active
enzymatic portion of the membrane and the second electroactive
surface is disposed beneath a non-enzymatic portion of the
membrane. Preferably, the sensor includes a physical diffusion
barrier, and the first and second electroactive surfaces are
disposed sufficiently close together that the first and second
noise components (detected by the first and second working
electrodes) are substantially equivalent. In some embodiments, the
distance between the first and second electroactive surfaces is
less than about twice the thickness of the membrane. In some
embodiments, the first and second electroactive surfaces are spaced
a distance that is less than or equal to about a crosstalk
diffusion distance of a measurable species, such as the
H.sub.2O.sub.2 produced in the active enzymatic portion of the
sensor membrane. In some embodiments, the physical diffusion
barrier is configured and arranged to physically block some
diffusion of the measurable species from the active enzymatic
portion of the membrane to the second electroactive surface (e.g.,
crosstalk). In preferred embodiments, the physical diffusion
barrier blocks a substantial amount of the measurable species, such
that there is substantially no signal associated with crosstalk
measured at the second working electrode. In some embodiments, the
physical diffusion barrier is a discontinuous portion of the
membrane disposed between the first and second electroactive
surfaces. In some embodiments, the physical diffusion barrier is a
first barrier layer formed on the first electrode and a second
barrier layer formed on the second electrode, wherein the first and
second barrier layers are independently formed. In some
embodiments, the physical diffusion barrier includes a first
resistance domain formed on the first electrode and a second
resistance domain formed on the second electrode. Preferably, the
first and second resistance domains reduce diffusion of the
measurable species (e.g., crosstalk) by at least 2-fold. In more
preferred embodiments, the diffusion of the measurable species is
reduced by at least 10-fold. In some embodiments, the membrane is
an insulator that insulates the first working electrode from the
second working electrodes. In some further embodiments, the first
and second areas are sufficiently large that the first and second
noise components are substantially equivalent.
[0707] Sensor Electronics
[0708] The analyte sensor system has electronics, also referred to
as a "computer system" that can include hardware, firmware, and/or
software that enable measurement and processing of data associated
with analyte levels in the host. In one exemplary embodiment, the
electronics include a potentiostat, a power source for providing
power to the sensor, and other components useful for signal
processing. In another exemplary embodiment, the electronics
include an RF module for transmitting data from sensor electronics
to a receiver remote from the sensor. In another exemplary
embodiment, the sensor electronics are wired to a receiver, which
records the data and optionally transmits the data to a remote
location, such as but not limited to a nurse's station, for
tracking the host's progress and to alarm the staff is a
hypoglycemic episode occurs. In another exemplary embodiment, the
sensor electronics include a processor module configured to and/or
comprises programming for processing sensor data, as described
elsewhere herein. In some exemplary embodiments, the sensor
electronics include a receiving module for receiving sensor
signals, such as but not limited to from the working electrode(s),
and/or externally provided reference data points. In some
embodiments, the processor module can include the receiving module.
The processor module and the receiving module can be located
together and/or in any combination of sensor electronics local to
and/or remote from the sensor.
[0709] Various components of the electronics of the sensor system
can be disposed on or proximal to the analyte sensor, such as but
not limited to disposed on the fluid coupler 20 of the system, such
as the embodiment shown in FIG. 1A. In another embodiment, wherein
the sensor is integrally formed on the catheter (e.g., see FIG. 2A)
and the electronics are disposed on or proximal to the connector
218. In some embodiments, only a portion of the electronics (e.g.,
the potentiostat) is disposed on the device (e.g., proximal to the
sensor), while the remaining electronics are disposed remotely from
the device, such as on a stand or by the bedside. In a further
embodiment, a portion of the electronics can be disposed in a
central location, such as a nurse's station.
[0710] In additional embodiments, some or all of the electronics
can be in wired or wireless communication with the sensor and/or
other portions of the electronics. For example, a potentiostat
disposed on the device can be wired to the remaining electronics
(e.g., a processor, a recorder, a transmitter, a receiver, etc.),
which reside on the bedside. In another example, some portion of
the electronics is wirelessly connected to another portion of the
electronics, such as by infrared (IR) or RF. In one embodiment, a
potentiostat resides on the fluid coupler and is connected to a
receiver by RF; accordingly, a battery, RF transmitter, and/or
other minimally necessary electronics are provided with the fluid
coupler and the receiver includes an RF receiver.
[0711] Preferably, the potentiostat is operably connected to the
electrode(s) (such as described above), which biases the sensor to
enable measurement of a current signal indicative of the analyte
concentration in the host (also referred to as the analog portion).
In some embodiments, the potentiostat includes a resistor that
translates the current into voltage. In some alternative
embodiments, a current to frequency converter is provided that is
configured to continuously integrate the measured current, for
example, using a charge counting device.
[0712] In some embodiments, the electronics include an A/D
converter that digitizes the analog signal into a digital signal,
also referred to as "counts" for processing. Accordingly, the
resulting raw data stream in counts, also referred to as raw sensor
data, is directly related to the current measured by the
potentiostat.
[0713] Typically, the electronics include a processor module that
includes the central control unit that controls the processing of
the sensor system. In some embodiments, the processor module
includes a microprocessor, however a computer system other than a
microprocessor can be used to process data as described herein, for
example an ASIC can be used for some or all of the sensor's central
processing. The processor typically provides semi-permanent storage
of data, for example, storing data such as sensor identifier (ID)
and programming to process data streams (for example, programming
for data smoothing and/or replacement of signal artifacts such as
is described in U.S. Patent Publication No. US-2005-0043598-A1).
The processor additionally can be used for the system's cache
memory, for example for temporarily storing recent sensor data. In
some embodiments, the processor module comprises memory storage
components such as ROM, RAM, dynamic-RAM, static-RAM, non-static
RAM, EEPROM, rewritable ROMs, flash memory, and the like.
[0714] In some embodiments, the processor module comprises a
digital filter (e.g., programming), for example, an infinite
impulse response (IIR) or finite impulse response (FIR) filter,
configured to smooth the raw data stream from the A/D converter.
Generally, digital filters are programmed to filter data sampled at
a predetermined time interval (also referred to as a sample rate).
In some embodiments, wherein the potentiostat is configured to
measure the analyte at discrete time intervals, these time
intervals determine the sample rate of the digital filter. In some
alternative embodiments, wherein the potentiostat is configured to
continuously measure the analyte, for example, using a
current-to-frequency converter as described above, the processor
module can be programmed to request a digital value from the A/D
converter at a predetermined time interval, also referred to as the
acquisition time. In these alternative embodiments, the values
obtained by the processor are advantageously averaged over the
acquisition time due the continuity of the current measurement.
Accordingly, the acquisition time determines the sample rate of the
digital filter. In preferred embodiments, the processor module is
configured with a programmable acquisition time, namely, the
predetermined time interval for requesting the digital value from
the A/D converter is programmable by a user within the digital
circuitry of the processor module. An acquisition time of from
about 2 seconds to about 512 seconds is preferred; however any
acquisition time can be programmed into the processor module. A
programmable acquisition time is advantageous in optimizing noise
filtration, time lag, and processing/battery power.
[0715] In some embodiments, the processor module is configured to
and/or comprises programming to build the data packet for
transmission to an outside source, for example, an RF transmission
to a receiver. Generally, the data packet comprises a plurality of
bits that can include a preamble, a unique identifier identifying
the electronics unit, the receiver, or both, (e.g., sensor ID
code), data (e.g., raw data, filtered data, and/or an integrated
value) and/or error detection or correction. Preferably, the data
(transmission) packet has a length of from about 8 bits to about
128 bits, preferably about 48 bits; however, larger or smaller
packets can be desirable in certain embodiments. The processor
module can be configured to transmit any combination of raw and/or
filtered data. In one exemplary embodiment, the transmission packet
contains a fixed preamble, a unique ID of the electronics unit, a
single five-minute average (e.g., integrated) sensor data value,
and a cyclic redundancy code (CRC).
[0716] In some embodiments, the processor module further comprises
a transmitter portion that determines the transmission interval of
the sensor data to a receiver, and the like. In some embodiments,
the transmitter portion, which determines the interval of
transmission, is configured to be programmable. In one such
embodiment, a coefficient can be chosen (e.g., a number of from
about 1 to about 100, or more), wherein the coefficient is
multiplied by the acquisition time (or sampling rate), such as
described above, to define the transmission interval of the data
packet. Thus, in some embodiments, the transmission interval is
programmable from about 2 seconds to about 850 minutes, more
preferably from about 30 second to about 5 minutes; however, any
transmission interval can be programmable or programmed into the
processor module. However, a variety of alternative systems and
methods for providing a programmable transmission interval can also
be employed. By providing a programmable transmission interval,
data transmission can be customized to meet a variety of design
criteria (e.g., reduced battery consumption, timeliness of
reporting sensor values, etc.)
[0717] In some embodiments, the processor is further configured to
and/or further comprises programming to perform the processing,
such as storing data, analyzing data streams, calibrating analyte
sensor data, estimating analyte values, comparing estimated analyte
values with time corresponding measured analyte values, analyzing a
variation of estimated analyte values, downloading data, and
controlling the user interface by providing analyte values,
prompts, messages, warnings, alarms, and the like. In such cases,
the processor includes hardware and software that performs the
processing described herein, for example flash memory provides
permanent or semi-permanent storage of data, storing data such as
sensor ID, receiver ID, and programming to process data streams
(for example, programming for performing estimation and other
algorithms described elsewhere herein) and random access memory
(RAM) stores the system's cache memory and is helpful in data
processing. Alternatively, some portion of the data processing
(such as described with reference to the processor elsewhere
herein) can be accomplished at another (e.g., remote) processor and
can be configured to be in wired or wireless connection
therewith.
[0718] In some embodiments, an output module, which is integral
with and/or operatively connected with the processor, includes
programming for generating output based on the data stream received
from the sensor system and it's processing incurred in the
processor. In some embodiments, output is generated via a user
interface.
[0719] In some embodiments, a user interface is provided integral
with (e.g., on the patient inserted medical device), proximal to
(e.g., a receiver near the medical device including bedside or on a
stand), or remote from the sensor electronics (e.g., at a central
station such as a nurse's station), wherein the user interface
comprises a keyboard, speaker, vibrator, backlight, liquid crystal
display (LCD) screen, and one or more buttons. The components that
comprise the user interface include controls to allow interaction
of the user with the sensor system. The keyboard can allow, for
example, input of user information, such as mealtime, exercise,
insulin administration, customized therapy recommendations, and
reference analyte values. The speaker can produce, for example,
audible signals or alerts for conditions such as present and/or
estimated hyperglycemic or hypoglycemic conditions. The vibrator
can provide, for example, tactile signals or alerts for reasons
such as described with reference to the speaker, above. The
backlight can be provided, for example, to aid a user in reading
the LCD in low light conditions. The LCD can be provided, for
example, to provide the user with visual data output, such as is
described in U.S. Patent Publication No. US-2005-0203360-A1. In
some embodiments, the LCD is a touch-activated screen, enabling
each selection by a user, for example, from a menu on the screen.
The buttons 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.
[0720] In some embodiments, prompts or messages can be displayed on
the user interface to convey information to the user, such as
reference outlier values, requests for reference analyte values,
therapy recommendations, deviation of the measured analyte values
from the estimated analyte values, and the like. Additionally,
prompts can be displayed to guide the user through calibration or
trouble-shooting of the calibration.
[0721] Additionally, data output from the output module can provide
wired or wireless, one- or two-way communication between the user
interface and an external device. The external device can be any
device that wherein interfaces or communicates with the user
interface. In some embodiments, the external device is a computer,
and the system is able to download historical data for
retrospective analysis by the patient or physician, for example. In
some embodiments, the external device is a modem or other
telecommunications station, and the system is able to send alerts,
warnings, emergency messages, and the like, via telecommunication
lines to another party, such as a doctor or family member. In some
embodiments, the external device is an insulin pen, and the system
is able to communicate therapy recommendations, such as insulin
amount and time to the insulin pen. In some embodiments, the
external device is an insulin pump, and the system is able to
communicate therapy recommendations, such as insulin amount and
time to the insulin pump. The external device can include other
technology or medical devices, for example pacemakers, implanted
analyte sensor patches, other infusion devices, telemetry devices,
and the like.
[0722] The user interface, including keyboard, buttons, a
microphone (not shown), and optionally the external device, can be
configured to allow input of data. Data input can be helpful in
obtaining information about the patient (for example, meal time,
insulin administration, and the like), receiving instructions from
a physician (for example, customized therapy recommendations,
targets, and the like), and downloading software updates, for
example. Keyboard, 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 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, and 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, such as
medication taken, surgical procedures, and the like, which can be
helpful in linking to an individual's physiological patterns, or
other data processing. In another embodiment, a temperature sensor
and/or heart rate monitor can provide information helpful in
linking activity, metabolism, and glucose excursions of an
individual. While a few examples of data input have been provided
here, a variety of information can be input, which can be helpful
in data processing.
[0723] Algorithms
[0724] In some embodiments, calibration of an analyte sensor can be
required, which includes data processing that converts sensor data
signal into an estimated analyte measurement that is meaningful to
a user. In general, the sensor system has a computer system (e.g.,
within the electronics) that receives sensor data (e.g., a data
stream), including one or more time-spaced sensor data points,
measured by the sensor. The sensor data point(s) can be smoothed
(filtered) in certain embodiments using a filter, for example, a
finite impulse response (FIR) or infinite impulse response (IIR)
filter. During the initialization of the sensor, prior to initial
calibration, the system can receive and store uncalibrated sensor
data, however it can be configured to not display any data to the
user until initial calibration and, optionally, stabilization of
the sensor has been established. In some embodiments, the data
stream can be evaluated to determine sensor break-in (equilibration
of the sensor in vitro or in vivo).
[0725] In some embodiments, the system is configured to receive
reference data from a reference analyte monitor, including one or
more reference data points, also referred to as calibration
information in some embodiments. The monitor can be of any suitable
configuration. For example, in one embodiment, the reference
analyte points can comprise results from a self-monitored blood
analyte test (e.g., from a finger stick test, YSI, Beckman Glucose
Analyzer, and the like), such as those described in U.S. Pat. Nos.
6,045,567, 6,156,051, 6,197,040, 6,284,125, 6,413,410, and
6,733,655. In one such embodiment, the user can administer a
self-monitored blood analyte test to obtain an analyte value (e.g.,
point) using any suitable analyte sensor, and then enter the
numeric analyte value into the computer system. In another such
embodiment, a self-monitored blood analyte test comprises a wired
or wireless connection to the computer system so that the user
simply initiates a connection between the two devices, and the
reference analyte data is passed or downloaded between the
self-monitored blood analyte test and the system. In yet another
such embodiment, the self-monitored analyte test is integral with
the receiver so that the user simply provides a blood sample to the
receiver, and the receiver runs the analyte test to determine a
reference analyte value.
[0726] In some alternative embodiments, the reference data is based
on sensor data from another substantially continuous analyte sensor
such as described herein, or another type of suitable continuous
analyte sensor. In an embodiment employing a series of two or more
continuous sensors, the sensors can be employed so that they
provide sensor data in discrete or overlapping periods. In such
embodiments, the sensor data from one continuous sensor can be used
to calibrate another continuous sensor, or be used to confirm the
validity of a subsequently employed continuous sensor.
[0727] In some embodiments, the sensor system is coupled to a blood
analysis device that periodically or intermittently collects a
sample of the host's blood (e.g., through the sensor system) and
measures the host's glucose concentration. In some embodiments, the
blood analysis device collects a blood sample from the host about
every 30 minutes, every hour, or every few hours (e.g., 2, 3, 4, 5,
6, 8, 9 or 10 hours or longer). In other embodiments, the blood
analysis device can be activated manually (e.g., by a healthcare
worker) to collect and analyze a blood sample from the host. The
glucose concentration data generated by the blood analysis device
can be used by the sensor system for calibration data. In some
embodiments, the sensor system can electronically receive (either
wired or wirelessly) these calibration data (from the blood
analysis device). In other embodiments, these calibration data can
be entered into the sensor system (e.g., sensor system electronics)
by hand (e.g., manually entered by a healthcare worker).
[0728] In some embodiments, the sensor system is provided with one
or more calibration solutions (e.g., glucose solutions). In some
embodiments, the sensor is shipped in a calibration solution (e.g.,
soaked). The sensor is activated to calibrate itself (using the
calibration solution in which it was shipped) before insertion into
the host. In some embodiments, the sensor is shipped (e.g., soaked
or dry) with one or more vials of calibration solution. The sensor
can be soaked (e.g., sequentially) in the vial(s) of calibration
solution; calibration data points collected and the sensor
calibrated using those calibration points, before inserting the
sensor into the host.
[0729] In one exemplary embodiment, the sensor is a glucose sensor,
and it is shipped soaking in a sterile 50 mg/dl glucose solution
with two accompanying calibration solutions (e.g., 100 mg/dl and
200 mg/dl sterile glucose solutions). Prior to insertion into the
host, calibration data points are collected with the sensor in the
50 mg/dl, 100 mg/dl and 200 mg/dl glucose solutions respectively.
The sensor system can be calibrated using the collected calibration
data points (e.g., using regression as described in more detail
elsewhere herein). In an alternative exemplary embodiment, the
sensor is shipped dry (e.g., not soaking in a solution or buffer)
with at least one calibration solution, for calibrating the sensor
prior to insertion into the host. In some embodiments, a hand held
glucose monitor (e.g., SMBG device described herein) can test the
calibration solutions to generate calibration data points, which
are transferred electronically or manually to the sensor system for
calibration.
[0730] In some embodiments, a data matching module, also referred
to as the processor module, is configured to and/or comprises
programming to matches reference data (e.g., one or more reference
analyte data points) with substantially time corresponding sensor
data (e.g., one or more sensor data points) to provide one or more
matched data pairs. One reference data point can be matched to one
time corresponding sensor data point to form a matched data pair.
Alternatively, a plurality of reference data points can be averaged
(e.g., equally or non-equally weighted average, mean-value, median,
and the like) and matched to one time corresponding sensor data
point to form a matched data pair, one reference data point can be
matched to a plurality of time corresponding sensor data points
averaged to form a matched data pair, or a plurality of reference
data points can be averaged and matched to a plurality of time
corresponding sensor data points averaged to form a matched data
pair.
[0731] In some embodiments, a calibration set module, also referred
to as the calibration module or processor module, is configured to
and/or comprises programming to form an initial calibration set
from a set of one or more matched data pairs, which are used to
determine the relationship between the reference analyte data and
the sensor analyte data. The matched data pairs, which make up the
initial calibration set, can be selected according to predetermined
criteria. The criteria for the initial calibration set can be the
same as, or different from, the criteria for the updated
calibration sets. In certain embodiments, the number (n) of data
pair(s) selected for the initial calibration set is one. In other
embodiments, n data pairs are selected for the initial calibration
set wherein n is a function of the frequency of the received
reference data points. In various embodiments, two data pairs make
up the initial calibration set or six data pairs make up the
initial calibration set. In an embodiment wherein a substantially
continuous analyte sensor provides reference data, numerous data
points are used to provide reference data from more than 6 data
pairs (e.g., dozens or even hundreds of data pairs). In one
exemplary embodiment, a substantially continuous analyte sensor
provides 288 reference data points per day (every five minutes for
twenty-four hours), thereby providing an opportunity for a matched
data pair 288 times per day, for example. While specific numbers of
matched data pairs are referred to in the preferred embodiments,
any suitable number of matched data pairs per a given time period
can be employed.
[0732] In some embodiments, a conversion function module, also
referred to as the conversion module or processor module, is
configured to and/or comprises programming to use the calibration
set to create a conversion function. The conversion function
substantially defines the relationship between the reference
analyte data and the analyte sensor data.
[0733] A variety of known methods can be used with the preferred
embodiments to create the conversion function from the calibration
set. In one embodiment, wherein a plurality of matched data points
form the calibration set, a linear least squares regression is used
to calculate the conversion function; for example, this regression
calculates a slope and an offset using the equation y=mx+b. A
variety of regression or other conversion schemes can be
implemented herein.
[0734] In some alternative embodiments, the sensor is a
dual-electrode system. In one such dual-electrode system, a first
electrode functions as a hydrogen peroxide sensor including a
membrane system containing glucose-oxidase disposed thereon, which
operates as described herein. A second electrode is a hydrogen
peroxide sensor that is configured similar to the first electrode,
but with a modified membrane system (with the enzyme domain
removed, for example). This second electrode provides a signal
composed mostly of the baseline signal, b.
[0735] In some dual-electrode systems, the baseline signal is
(electronically or digitally) subtracted from the glucose signal to
obtain a glucose signal substantially without baseline.
Accordingly, calibration of the resultant difference signal can be
performed by solving the equation y=mx with a single paired
measurement. Calibration of the implanted sensor in this
alternative embodiment can be made less dependent on the
values/range of the paired measurements, less sensitive to error in
manual blood glucose measurements, and can facilitate the sensor's
use as a primary source of glucose information for the user. U.S.
Patent Publication No. US-2005-0143635-A1 describes systems and
methods for subtracting the baseline from a sensor signal.
[0736] In some alternative dual-electrode system embodiments, the
analyte sensor is configured to transmit signals obtained from each
electrode separately (e.g., without subtraction of the baseline
signal). In this way, the receiver can process these signals to
determine additional information about the sensor and/or analyte
concentration. For example, by comparing the signals from the first
and second electrodes, changes in baseline and/or sensitivity can
be detected and/or measured and used to update calibration (e.g.,
without the use of a reference analyte value). In one such example,
by monitoring the corresponding first and second signals over time,
an amount of signal contributed by baseline can be measured. In
another such example, by comparing fluctuations in the correlating
signals over time, changes in sensitivity can be detected and/or
measured.
[0737] In some alternative embodiments, the processor module is
configured to and/or comprises programming to use a regression
equation y=mx+b to calculate the conversion function; however,
prior information can be provided for m and/or b, thereby enabling
calibration to occur with fewer paired measurements. In one
calibration technique, prior information (e.g., obtained from in
vivo or in vitro tests) determines a sensitivity of the sensor
and/or the baseline signal of the sensor by analyzing sensor data
from measurements taken by the sensor (e.g., prior to inserting the
sensor). For example, if there exists a predictive relationship
between in vitro sensor parameters and in vivo parameters, then
this information can be used by the calibration procedure. For
example, if a predictive relationship exists between in vitro
sensitivity and in vivo sensitivity, m.apprxeq.f(m.sub.in vitro),
then the predicted m can be used, along with a single matched pair,
to solve for b (b=y-mx). If, in addition, b can be assumed=0, for
example with a dual-electrode configuration that enables
subtraction of the baseline from the signal such as described
above, then both m and b are known a priori, matched pairs are not
needed for calibration, and the sensor can be completely calibrated
e.g. without the need for reference analyte values (e.g. values
obtained after implantation in vivo.)
[0738] In another alternative embodiment, prior information can be
provided to guide or validate the baseline (b) and/or sensitivity
(m) determined from the regression analysis. In this embodiment,
boundaries can be set for the regression line that defines the
conversion function such that working sensors are calibrated
accurately and easily (with two points), and non-working sensors
are prevented from being calibrated. If the boundaries are drawn
too tightly, a working sensor may not enter into calibration.
Likewise, if the boundaries are drawn too loosely, the scheme can
result in inaccurate calibration or can permit non-working sensors
to enter into calibration. For example, subsequent to performing
regression, the resulting slope and/or baseline are tested to
determine whether they fall within a predetermined acceptable
threshold (boundaries). These predetermined acceptable boundaries
can be obtained from in vivo or in vitro tests (e.g., by a
retrospective analysis of sensor sensitivities and/or baselines
collected from a set of sensors/patients, assuming that the set is
representative of future data).
[0739] In some alternative embodiments, the sensor system does not
require initial and/or update calibration by the host; in these
alternative embodiments, also referred to as "zero-point
calibration" embodiments, use of the sensor system without
requiring a reference analyte measurement for initial and/or update
calibration is enabled. In general, the systems and methods of the
preferred embodiments provide for stable and repeatable sensor
manufacture, particularly when tightly controlled manufacturing
processes are utilized. Namely, a batch of sensors of the preferred
embodiments can be designed with substantially the same baseline
(b) and/or sensitivity (m) (+/-10%) when tested in vitro.
Additionally, the sensor of the preferred embodiments can be
designed for repeatable m and b in vivo. Thus, an initial
calibration factor (conversion function) can be programmed into the
sensor (sensor electronics and/or receiver electronics) that
enables conversion of raw sensor data into calibrated sensor data
solely using information obtained prior to implantation (namely,
initial calibration does not require a reference analyte value).
Additionally, to obviate the need for recalibration (update
calibration) during the life of the sensor, the sensor is designed
to minimize drift of the sensitivity and/or baseline over time in
vivo. Accordingly, the preferred embodiments can be manufactured
for zero point calibration.
[0740] In some embodiments, a sensor data transformation module,
also referred to as the calibration module, conversion module, or
processor module, is configured to and/or comprises programming to
use the conversion function to transform sensor data into
substantially real-time analyte value estimates, also referred to
as calibrated data, or converted sensor data, as sensor data is
continuously (or intermittently) received from the sensor. For
example, the sensor data, which can be provided to the receiver in
"counts," is translated in to estimate analyte value(s) in mg/dL.
In other words, the offset value at any given point in time can be
subtracted from the raw value (e.g., in counts) and divided by the
slope to obtain the estimate analyte value:
mg / dL = ( r a w v alue - offset ) slope ##EQU00001##
[0741] In some embodiments, an output module is configured to
and/or comprises programming to provide output to the user via the
user interface. The output is representative of the estimated
analyte value, which is determined by converting the sensor data
into a meaningful analyte value. User output can be in the form of
a numeric estimated analyte value, an indication of directional
trend of analyte concentration, and/or a graphical representation
of the estimated analyte data over a period of time, for example.
Other representations of the estimated analyte values are also
possible, for example audio and tactile.
[0742] In some embodiments, annotations are provided on the graph;
for example, bitmap images are displayed thereon, which represent
events experienced by the host. For example, information about
meals, medications, insulin, exercise, sensor insertion, sleep, and
the like, can be obtained by the receiver (by user input or receipt
of a transmission from another device) and displayed on the
graphical representation of the host's glucose over time. It is
believed that illustrating a host's life events matched with a
host's glucose concentration over time can be helpful in educating
the host to his or her metabolic response to the various
events.
[0743] In yet another alternative embodiment, the sensor utilizes
one or more additional electrodes to measure an additional analyte.
Such measurements can provide a baseline or sensitivity value for
use in calibrating the sensor. Furthermore, baseline and/or
sensitivity values can be used to trigger events such as digital
filtering of data or suspending display of data, all of which are
described in more detail in U.S. Patent Publication No.
US-2005-0143635-A1.
[0744] In one exemplary embodiment, the sensor can be calibrated by
a calibration solution. For example, after the sensor system has
been inserted into the host, a calibration solution can be injected
so as to pass across the electroactive surface of the
analyte-measuring electrode and the sensor calibrated thereby. For
example, the saline drip can be changed to a known IV glucose or
dextrose solution (e.g., D50--a 50% dextrose solution, or D5 W--a
5% dextrose solution). In one embodiment, a known volume of D5 W is
infused into the host at a known rate over a predetermined period
of time (e.g., 5, 10, 15 or 20 minutes, or for shorter or longer
periods). During and/or after the period of infusion, the sensor
measures the signal at the analyte-measuring working electrode. The
system, knowing the specifications of the infused calibration
solution (also referred to as a calibration information in some
embodiments), can calibrate the signal to obtain host's glucose
concentration as is appreciated by one skilled in the art. In a
further embodiment, two or more glucose or dextrose solutions can
be infused, with a corresponding signal being measured during each
infusion, to provide additional data for sensor calibration.
Calibration can be performed after the sensor has first been
inserted into the host, after a break-in time, at two or more
different levels (high/low), regularly, intermittently, in response
to sensor drift/shift, automatically or any other time when
calibration is required. In some alternative embodiments,
calibration can be determined during sensor break-in, such as
described in more detail elsewhere herein.
[0745] In some circumstances, catheters are flushed with saline.
For example, the analyte sensor system of the preferred embodiments
can be flushed with saline prior to application of control
solutions, after which a predetermined amount of glucose solution
is flushed by the sensor, as described above, and the sensor is
calibrated there from.
[0746] In still another embodiment, a blood sample can be withdrawn
from an artery or vein, and used to calibrate the sensor, for
example, by using a hand-held glucose meter, by an automatic
extracorporeal glucose sensor such as but not limited to in
conjunction with an automated bedside clinical chemistry device, or
by sending the blood sample to the clinical laboratory for glucose
analysis, after which the data is input (e.g., into the electronics
associated with the sensor system).
[0747] In some embodiments, the sensor can be calibrated (and/or
re-calibrated) during use (after initial calibration), for example,
by withdrawing one or more blood samples (also referred to as
calibration information in some embodiments), through the catheter
(see FIGS. 1 and 2) and used for calibration of the sensor, such as
by measuring the glucose concentration of the blood sample with an
additional system, such as but not limited to a hand-held glucose
meter, optical methods or additional electrochemical methods. Blood
samples can be withdrawn manually or automatically; additionally or
alternatively, blood samples are withdrawn at regular intervals or
at selected times, for example, using an extracorporeal blood
analysis device as described herein.
[0748] In another embodiment of sensor calibration (and/or
re-calibration) during use, a calibration solution (e.g., 40 mg/dL
equivalent glucose, D540 or D5 W) can be flushed through or by the
sensor to enable calibration of the sensor (e.g., at one time,
intermittently, or continuously), such as described in more detail
above. In these embodiments, calibration solution can be flushed
manually or automatically through the system; additionally or
alternatively, calibration solution can be flushed at regular
intervals or at selected times. In one exemplary embodiment, the
system can be provided with a dual lumen, one for saline and
another for the control solution. Additionally, the system is
configured to automatically switch from the saline to control
solution and perform the real-time system calibration, and then
switch back to the saline solution.
[0749] Calibration Systems and Methods for Dual-Electrode
Sensors
[0750] As described herein, continuous analyte sensors define a
relationship between a sensor-generated signal 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
changes can occur during in vivo sensor use, which requires
calibration updates (e.g., recalibration). Generally, any physical
properties of the sensor or the fluid surrounding the sensor can
influence diffusion or transport of molecules through the membrane,
and thereby produce fluctuations in sensitivity and/or baseline,
which in turn affect the sensor's calibration. These physical
properties include, but are not limited to, blockage of sensor
surface area due to cells and/or blood clotting at the membrane,
biofouling, blood flow/sheer rate, blood pH, temperature,
hematocrit, interfering drugs in the host's system, certain
metabolic processes, disrupted host electrolyte balance due to
disease and/or trauma, thickness and/or components of the sensor's
membrane system, and the like.
[0751] In one aspect of the preferred embodiments, systems and
methods are provided for measuring changes in sensitivity m, also
referred to as changes in solute transport or membrane changes, of
an analyte sensor implanted in a host over a time period.
Preferably, the sensitivity value 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 on the glucose sensor. While not
wishing to be bound by theory, it is believed that by monitoring
the sensitivity m over a time period, a change associated with
solute transport through the membrane system (e.g., diffusion there
through) can be measured and used as an indication of a sensitivity
change in the analyte measurement. In other words, a membrane
monitor is provided, which is capable of monitoring changes in the
membrane surrounding an implantable device, thereby enabling the
measurement of sensitivity changes of an analyte sensor over
time.
[0752] In some embodiments, the analyte sensor is provided with an
auxiliary electrode (e.g., a second working electrode) configured
as a transport-measuring electrode disposed beneath the membrane
system. 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 through the membrane system. 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.
[0753] 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
values that can be used as to qualify or quantify solute transport
through the membrane of the analyte sensor.
[0754] In one embodiment of a glucose sensor, the
transport-measuring electrode is configured to measure urea, which
is a water-soluble constant analyte that is known to react directly
or indirectly at a hydrogen peroxide sensing electrode (similar to
the working electrode of the glucose sensor example described in
more detail above). In one exemplary implementation wherein urea is
directly measured by the transport-measuring electrode, the glucose
sensor comprises a membrane system as described in more detail
above, however, does not include an active interference domain or
active enzyme directly above the transport-measuring electrode,
thereby allowing the urea to pass through the membrane system to
the electroactive surface for measurement thereon. In one
alternative exemplary implementation wherein urea is indirectly
measured by the transport-measuring electrode, the glucose sensor
comprises a membrane system as described in more detail above, and
further includes an active uricase oxidase domain located directly
above the transport-measuring electrode, thereby allowing the urea
to react at the enzyme and produce hydrogen peroxide, which can be
measured at the electroactive surface thereon.
[0755] In some embodiments, the change in sensitivity m is measured
by measuring a change in oxygen concentration 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 (eliminating the need
for a separate auxiliary electrode), such as by switching the
applied potential from +0.6 mV to -0.6 mV. In another embodiment,
the auxiliary electrode is configured as an oxygen-measuring
electrode. In some embodiments, a third electrode can be configured
as an oxygen-measuring electrode. In another embodiment, an oxygen
sensor (not shown) is added to the glucose sensor, as is
appreciated by one skilled in the art, eliminating the need for an
auxiliary electrode.
[0756] In some embodiments, sensitivity changes in an intravascular
dual-electrode continuous analyte sensor can be provided via a
reference sensor, such as an oxygen sensor, as described in the
section entitled "Optical Detection." In some embodiments,
auto-calibration (e.g., without a manual, external (to the system)
reference value) is enabled by exposing the dual-electrode sensor
and the reference sensor simultaneously to a reference/calibration
solution, whereby reference data is provided for calibration of the
sensor data. Advantageously, a dual-electrode continuous analyte
sensor is configured to measure baseline b, and changes in
sensitivity m are measured by exposure of the dual-electrode sensor
to the reference/calibration solution. In some embodiments, the
system is configured for "on demand" auto-calibration, such as via
configuring the system such that a user can initiate (e.g.,
command) auto-calibration via a user interface (e.g., via selection
from a menu, pressing a pre-programmed button and the like).
[0757] 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.
[0758] It should be appreciated by one skilled in the art that in
some embodiments, the implementation of sensitivity values 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.
[0759] In some embodiments, the signal from the oxygen measuring
electrode may be digitally low-pass filtered (for example, with a
passband of 0-10.sup.-5 Hz, dc-24 hour cycle lengths) to remove
transient fluctuations in oxygen, due to local ischemia, postural
effects, periods of apnea, or the like. Since oxygen delivery to
tissues is held in tight homeostatic control, this filtered oxygen
signal should oscillate about a relatively constant. In the
interstitial fluid, it is thought that the levels are about
equivalent with venous blood (40 mmHg). Once implanted, changes in
the mean of the oxygen signal (for example, >5%) may be
indicative of change in transport through the membrane (change in
sensor sensitivity and/or baseline due to changes in solute
transport) and the need for system recalibration.
[0760] 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 for 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. Patent Publication
No. US-2005-0043598-A1, which is incorporated by reference in its
entirety herein, describes some methods of signal artifact
detection and replacement that may be useful such as described
herein.
[0761] 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.
[0762] In a second aspect the preferred embodiments, systems and
methods are provided for measuring baseline, namely non-glucose
related electroactive compounds in the host. Preferably the
auxiliary working electrode (e.g., second working electrode,
non-enzymatic working electrode) is configured to measure the
baseline of the analyte sensor over time. In some embodiments, the
glucose-measuring working electrode (e.g., first working electrode)
is a hydrogen peroxide sensor coupled to a membrane system
containing an active enzyme located above the electrode. In some
embodiments, the auxiliary working electrode (e.g., second working
electrode) is another hydrogen peroxide sensor that is configured
similar to the glucose-measuring working electrode however a
portion of the membrane system above the base-measuring electrode
does not have active enzyme therein, such as described in more
detail with reference to FIG. 3D. The auxiliary working electrode
provides a signal substantially comprising the baseline signal, b,
which can be (for example, electronically or digitally) subtracted
from the glucose signal obtained from the glucose-measuring working
electrode to obtain the signal contribution due to glucose only
according to the following equation:
Signal.sub.glucose only=Signal.sub.glucose-measuring working
electrode-Signal.sub.baseline-measuring working electrode
[0763] 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.
[0764] One aspect the preferred embodiments provides for a
simplified calibration technique, wherein the variability of the
baseline has been eliminated (namely, subtracted). Namely,
calibration of the resultant differential signal
(Signal.sub.glucose only) can be performed with a single matched
data pair by solving the following equation:
y=mx
[0765] 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.
[0766] In some embodiments, the glucose-measuring working electrode
(e.g., first working electrode) is a hydrogen peroxide sensor
coupled to a membrane system containing an active enzyme located
above the electrode, such as described in more detail above;
however the baseline signal is not subtracted from the glucose
signal for calibration of the sensor. Rather, multiple matched data
pairs are obtained in order to calibrate the sensor (for example
using y=mx+b) in a conventional manner, and the auxiliary/second
working electrode is used as an indicator of baseline shifts in the
sensor signal. Namely, the auxiliary/second working electrode 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/second working electrode signal as an
indicator of baseline shifts, recalibration requiring user
interaction (namely, new reference glucose values) can be minimized
due to timeliness and appropriateness of the requests. In some
embodiments, the sensor is re-calibrated responsive to a baseline
shifts exceeding a preselected threshold value. In some
embodiments, the sensor is calibrated repeatedly at a frequency
responsive to the rate-of-change of the baseline.
[0767] 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/second working electrode is
further utilized as an indicator of baseline shifts in the sensor
signal. While not wishing to be bound by theory, it is believed
that shifts in baseline may also correlate and/or be related to
changes in the sensitivity m of the glucose signal. Consequently, a
shift in baseline may be indicative of a change in sensitivity m.
Therefore, the auxiliary working electrode 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
(second) 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.
[0768] In yet another alternative embodiment, wherein a
dual-electrode analyte system is use, the baseline signal is
(electronically or digitally) subtracted from the glucose+baseline
signal to obtain a glucose signal substantially without baseline.
Accordingly, calibration of the resultant difference signal can be
performed by solving the equation y=mx using a sensitivity value
(m), which can be obtained from 1) the measured reference
(calibrant) solution, b) by pairing a reference analyte signal with
a reference analyte value (internal reference sensor example)
and/or 3) with a sensitivity value obtained a priori (e.g., during
sensor manufacture, such as but not limited to by testing in an
isotonic solution). Accordingly, calibration of the implanted
sensor in this embodiment can be less sensitive or insensitive to
user error associated with providing external reference
measurements, and can facilitate the sensor's use as a primary
source of glucose information for the user. However, a single
external reference value (e.g., from an external test device such
as SMBG and/or YSI testing of a host blood sample) can be used to
calibrate the sensor in some embodiments. U.S. Patent Publication
No. US-2005-0143635-A1 describes systems and methods for
subtracting the baseline from a sensor signal.
[0769] It is noted that, in some embodiments, infrequent new
matching data pairs (e.g., auto-calibration, on demand calibration)
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 membrane 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).
[0770] An additional advantage of the sensor of the preferred
embodiments includes providing a method for eliminating signal
effects of interfering species, which have conventionally been
problematic in electrochemical glucose sensors. Namely,
electrochemical sensors are subject to electrochemical reaction not
only with the hydrogen peroxide (or other analyte to be measured),
but additionally may react with other electroactive species that
are not intentionally being measured (for example, interfering
species), which cause a change in signal strength due to this
interference. In other words, interfering species are compounds
with an oxidation or reduction potential that overlap with the
analyte being measured. Interfering species such as acetaminophen,
ascorbate, and urate, are notorious in the art of glucose sensors
for producing inaccurate signal strength when they are not properly
controlled. Some glucose sensors utilize a membrane system that
blocks at least some interfering species, such as ascorbate and
urate. Unfortunately, it is difficult to find membranes that are
satisfactory or reliable in use, especially in vivo, which
effectively block all interferants and/or interfering species (for
example, see U.S. Pat. Nos. 4,776,944, 5,356,786, 5,593,852,
5,776,324, and 6,356,776).
[0771] 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.
[0772] In summary, the system and methods of the preferred
embodiments simplify the computation processes of calibration,
decreases the susceptibility introduced by user error in
calibration, and eliminates the effects of interfering species.
Accordingly, the sensor requires less interaction by the patient
(for example, less frequent calibration), increases patient
convenience (for example, few reference glucose values), and
improves accuracy (via simple and reliable calibration).
[0773] 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
membrane over time, elimination of erroneous signal due to
non-constant analyte-related signal so interfering species, and/or
self-diagnosis of the calibration for more intelligent
recalibration of the sensor.
[0774] Preferably, a dual-electrode sensor's working electrodes E1,
E2 should function identically, with identical sensitivity and/or
baseline measurements. However, in some circumstances, small
differences in the portions of the membrane at the first and second
working electrodes can result in slight differences in membrane
sensitivities (m) and/or the baselines (b) signal associated with
the working electrodes. While not wishing to be bound by theory, it
is believed that such small differences can arise during
manufacture, for example, when E1 and E2 have one or more separate
manufacturing steps. Additionally, the compositions of the enzyme
domains can be slightly different. For example, an E1 enzyme domain
can be somewhat more hydrophilic than an E2 enzyme domain
manufactured without any added enzyme. In some circumstances,
certain characteristics of the blood samples (e.g., pH, certain
medicaments in the host's circulatory system, temperature,
pO.sub.2) to which the sensor is exposed can, amplify the effects
of these differences. In some circumstances, these small
differences (between E1 and E2) can contribute to sensor
inaccuracies. In preferred embodiments, such sensor inaccuracies
can be avoided by use of a scaling factor (k) that is calculated by
evaluating the signal response at each of the working electrodes.
In some embodiments, the scaling factor is measured in vitro, prior
to sensor implantation.
[0775] In one preferred embodiment, a scaling factor (k) is
calculated by evaluating the signal response after at point at
which substantially all of the analyte present in a blood sample
should have been used up. FIG. 3J is a graph that illustrates
exemplary data collected upon exposure of a dual-electrode
continuous analyte sensor to a blood sample. The Y-axis represents
the signal generated and the X-axis represents time. The top graph
is data generated by the plus-enzyme working electrode (e.g., first
working electrode, E1). The bottom graph is time-corresponding data
generated by the minus-enzyme working electrode (e.g.,
non-enzymatic, second working electrode, E2). In general, when the
sensor is exposed to a blood sample, the E1 signal will increase
1302 until substantially all of the available analyte is used up
(e.g., at t1) by the enzyme at the plus-enzyme working electrode.
In general, as with most enzymes, when all of the substrate (e.g.,
analyte) is used up, the signal should plateau (e.g., line 1306).
However, in spite of the lack of substrate (e.g., analyte) for the
enzyme, the signal actually continues to increase a small amount,
as is shown by line 1308. While not wishing to be bound by theory,
it is believed that the signal increase 1310 is due to signals
caused by non-analyte-related electroactive species, which diffuse
through the membrane more slowly than the analyte. This signal
increase (line 1304) is also observed on the non-enzymatic working
electrode (e.g., E2). Accordingly, the signal response for E2,
during the time period of t1 to t2, is the difference between lines
1305 and 1304. The scaling factor (k, also referred to as the
"buildup ratio") can be determined by evaluating the signal
response at the two working electrodes (e.g., between t.sub.1 and
t2) using the formula:
k S e n s o r = Signal_response Enzyme Signal_response NoEnzyme
##EQU00002##
[0776] Accordingly, for the exemplary data shown in FIG. 3J, the
scaling factor (k) is equal to the ratio of the plus-enzyme signal
response 1310 to the minus-enzyme signal response 1312. In a
related embodiment, a scaling factor can be calculated by
evaluating data generated at the early portion of the curve, soon
after the switch from a wash/reference solution (e.g., saline,
glucose, etc.) to blood, such as between about 2 second and about 2
minutes after the switch from blood to non-bodily fluid. The
scaling factor can then be used to adjust the data (e.g.,
calibrate) for differences in membrane sensitivities, thereby
providing increased sensor accuracy. In some embodiments, the
dual-electrode sensor is a glucose sensor. However, dual-electrode
sensors can be configured to detect other analytes as described
elsewhere herein.
[0777] In some embodiments, the scaling factor can be determined by
evaluating the signal responses of the first and second working
electrodes E1, E2 during exposure of the sensor to a non-bodily
fluid (e.g., saline, reference/calibration solution, hydration
fluid, wash fluid, nutritional fluid, medicament, etc.). As
described elsewhere herein, an intravascularly implanted
dual-electrode analyte sensor can be washed and/or calibrated
between exposures to blood samples. To measure the signal response
at the working electrodes, the non-bodily fluid can be held
stagnant (e.g., substantially not moving) for a period of time
(e.g., from t1 to t2). Signal responses at the working electrodes,
during the time period, can then be evaluated.
[0778] FIG. 3K is a graph that illustrates exemplary data received
upon exposure of a dual-electrode sensor to a non-bodily fluid. The
Y-axis represents signal generated at the working electrodes and
the X-axis represents time. The top graph is data generated by the
plus-enzyme working electrode (e.g., first working electrode, E1).
The bottom graph is time-corresponding data generated by the
minus-enzyme working electrode (e.g., non-enzymatic, second working
electrode, E2). Starting at t=0, the flow of fluid over the
dual-electrode continuous analyte sensor is stopped, such that the
fluid is substantially stagnant (e.g., not moving). At the first
working electrode E1 (with enzyme), an increasing signal is
generated, as is represented by line 1314. An increasing signal is
also generated at the second working electrode E2 (no enzyme), as
is illustrated by line 1316. The E1 signal response (1318) is the
difference between lines 1315 and 1314 at t2. Similarly, the E2
signal response (1320) is the difference between lines 1317 and
1316 at t2. While not wishing to be bound by theory, it is believed
that the observed signal response is due to diffusion of
non-analyte-related electroactive species through the plus and
minus enzyme membrane portions, which are then detected at the
working electrodes. The sensor scaling factor can be calculated
using the equation described above.
[0779] In some embodiments, to improve sensor accuracy, a scaling
factor can be calculated by comparing the signal response of a test
sensor (k.sup.TestSensor) to the signal response of a "perfect
sensor" (k.sup.PerfectSensor), using the following formula:
Scaling Factor = k T e s t S e n s o r k PerfectSensor
##EQU00003##
[0780] The signal response (k.sup.PerfectSensor) for a perfect
dual-electrode sensor (can be determined empirically by testing a
plurality of sensors in the laboratory, such as by using methods
known in the art.
[0781] As described in more detail elsewhere herein, useful
information (e.g., sensitivity and/or scaling factor) can be
extrapolated from periods in which the signal is transient, for
example, during sensor break-in and/or during a period of signal
artifact (e.g., noise). In some embodiments, the scaling factor is
determined during electrochemical break-in of the sensor.
Additionally or alternatively, the scaling factor is determined
during a period of signal artifact, for example, wherein the flow
of fluid across the sensor manipulated (e.g., disrupted)
intentionally and/or accidentally (and detected). In one exemplary
embodiment, the flow control device of the preferred embodiment is
configured to jitter, reciprocate and/or dither in such a way so as
to more effectively wash the sensor; in this exemplary embodiment,
signal artifact is induced on the signal by the induced flow
turbulence, which can be used to obtain useful information by
transient analysis of the signal.
[0782] Due to the kinetics of the signal during these transient
events, a noise amplitude can be determined for each of the first
and second working electrodes of a dual electrode system, and the
noise amplitude compared to obtain a scaling factor. In one
embodiment, the scaling factor is determined by using a residual
analysis, wherein filtered (e.g., smoothed) data is compared to raw
data (e.g., in local and/or remote electronics) to obtain a signal
residual. In one such embodiment, a signal residual is calculated
as the difference between the filtered data and the raw data. For
example, at one time point (or one time period that is represented
by a single raw value and single filtered value), the filtered data
can be measured at 50,000 counts and the raw data can be measured
at 55,500 counts, which would result in a signal residual of 5,500
counts. In some embodiments, the residuals provide the noise
amplitude information, which can be compared to obtain a scaling
factor. However, in some embodiments, a stream of residuals (e.g.,
individual time points during a kinetic period of the signal) for
each of the first and second working electrodes are averaged (e.g.,
using a moving average, or the like), and compared, to provide
noise amplitude information for each of the first and second
working electrodes, which can be used to define a scaling
factor.
[0783] In some embodiments, the manufacturer determines a baseline
(e.g., b.sub.offset) and/or a scaling factor prior to sensor use in
a host, such as but not limited to testing in one or more reference
solutions, such as but not limited to an isotonic solution. The
prospectively determined baseline (e.g., b.sub.offset) and/or
scaling factor can be included with the sensor provided to the
user, such as by providing a calibration code that can be entered
(e.g., manually) into the system electronics, that can be
automatically detected by the system electronics upon sensor
coupling thereto (e.g., via a detectable memory), and the like,
similar to the manufacturer-provided calibration codes for glucose
test strips.
[0784] As a non-limiting example, in preferred embodiments, a
system for measuring an analyte, wherein differences in first and
second working electrodes is accounted for, is provided. In this
embodiment, the system includes a continuous analyte sensor, a
vascular access device, a receiving module, and a processing
module. The continuous analyte sensor is configured for exposure to
a host's circulatory system in vivo, such as via fluidly coupling
with a vascular access device in fluid contact with the host's
circulatory system. The continuous analyte sensor includes first
and second working electrodes E1, E2. The first working electrode
E1 is disposed beneath an enzymatic portion of a membrane system,
wherein the enzymatic portion includes an enzyme for detecting the
analyte. For example, if the analyte is glucose, the enzymatic
portion includes GOX. If the analyte is cholesterol, the enzyme is
a cholesterol-metabolizing enzyme. The second working electrode E2
is disposed beneath a non-enzymatic portion of the membrane system,
which includes either no enzyme or an inactive form of the enzyme.
For example, the enzyme can be inactivated by a variety of methods,
such as denaturing by heating, UV exposure, treatment with a
protease or a denaturing chemical, and the like. In some
embodiments, the enzyme layer of the membrane system over E2 (e.g.,
the electroactive surface) includes another protein, such as BSA or
ovalbumin, which is not involved in the metabolism of the
analyte.
[0785] The system includes a receiving module configured to receive
the signals from the working electrodes (e.g., a first signal from
E1 and a second signal from E2). As described elsewhere herein, the
first signal is associated with both the analyte and non-analyte
related electroactive compounds; the second signal is associated
with non-analyte related electroactive compounds. The non-analyte
related compounds have an oxidation/reduction potential that
substantially overlaps with the analyte's oxidation/reduction
potential. Accordingly, if the dual-electrode sensor is configured
to detect glucose, E1 detects a signal having components associated
with glucose and non-glucose species that have oxidation/reduction
potentials that substantially overlap with the oxidation and/or
reduction potential of glucose (sometimes referred to herein as a
first oxidation/reduction potential), and E2 detects a signal
related to the non-glucose species that have oxidation/reduction
potentials that substantially overlap with the oxidation and/or
reduction potential of glucose.
[0786] The system includes a processor module configured to and/or
comprising programming that processes the first and second signals
and to estimate a scaling factor. As described herein, the scaling
factor defines a relationship between the first and second working
electrodes (e.g., associated with the measured baseline of each
first and second working electrodes). Preferably, the processor
module processes the first and second signals using the scaling
factor, to thereby obtain a signal (e.g., a glucose value)
substantially without contribution due to non-analyte related
electroactive compounds. For example, wherein the equation b=kz
defines the relationship (scaling factor (k)) between the baseline
(b) of the first (enzymatic) working electrode and the baseline z
of the second (non-enzymatic) working electrode. A calibration
equation (y=mx+b) can be modified to include the scaling factor to
calibrate the sensor (y-kz=mx).
[0787] In some preferred embodiments, the system includes a flow
control device is configured to meter a flow of a fluid through the
vascular access device. In some embodiments, the fluid is a bodily
fluid and the flow control device is configured to withdraw a
sample of bodily fluid (e.g., blood) from the host such that the
sensor is contacted with the bodily fluid. In a further embodiment,
the processor module is configured to and/or comprises programming
that compares steady-state information of the first signal and
steady-state information of the second signal. In some embodiments,
the fluid is a non-bodily fluid and the flow control device is
configured to hold the non-bodily fluid substantially stagnant
during a time period, as described herein. In preferred
embodiments, the processor module is configured to and/or comprises
programming that compares a signal increase on each of the first
and second working electrodes during the time period during which
the non-bodily fluid is held stagnant, as described herein.
[0788] In preferred embodiments, a method for processing sensor
data from a dual-electrode continuous analyte sensor, including
estimating a scaling factor (k), is provided. The dual-electrode
sensor, as described herein, is configured for in vivo exposure to
a host's circulatory system. The dual-electrode continuous analyte
sensor is applied to the host, such as via fluidly coupling the
sensor to a fluid flow device. In some embodiments, the sensor is
configured for insertion into a catheter or is a part of the
catheter, as described above. In some embodiments, the sensor is
part of a connecting device, such as a Leur lock, which is fluidly
coupled to a catheter at a first end and to the rest of the fluid
flow device (e.g., via IV tubing), such that blood samples can be
withdrawn and contacted with the sensor. After the sensor has been
applied to the host, signals from the working electrodes can be
received, as described elsewhere herein. A scaling factor, which
defines a relationship between a the first and second working
electrodes, can be estimated from the received signals, and then
the scaling factor can be used to process the signals and thereby
to obtain a signal substantially without contribution due to
non-analyte related electroactive compounds. In some embodiments,
the scaling factor is determined while contacting the sensor with a
bodily fluid (see above), such as by comparing steady-state
information of the first signal and steady-state information of the
second signal. In some embodiments, the scaling factor is
determined while contacting the sensor with a substantially
stagnant non-bodily fluid, such as by comparing a signal increase
on each of the working electrodes during exposure to the
substantially stagnant non-bodily fluid.
[0789] While not wishing to be bound by theory, it is believed that
determination of a scaling factor as described herein provides a
number of advantages. First, sample collection/testing is
alternated with calibration and/or washing, sensor calibration is
continuous and biofouling is substantially reduced. Since there is
little biofouling, the sensor functions more rapidly (e.g.,
T.sub.90 is reached more rapidly). Since the sensor is continuously
calibrated during use (e.g., such that background is removed) the
user receives more accurate glucose information/values to be used
in making therapeutic decisions. Thus, it is substantially easier
and safer for the host to maintain tight control over his or her
glucose levels, which can result in a better quality of life and
reduced long-term diabetic complications.
[0790] In many circumstances, glucose sensors can be calibrated
using data provided either by an analyte testing device separate
from the continuous analyte sensor system. For example, points for
a continuous glucose sensor, one or more reference data may be
provided by testing a blood sample with a hand-held glucose meter
or with an YSI glucose test device. However, in some preferred
embodiments, a system, including a continuous analyte sensor
(single working electrode or dual working electrode), is configured
to provide one or more data points, with which the continuous
analyte sensor can be calibrated, without the use of a separate
(e.g., external to the system) device and/or testing of reference
fluids.
[0791] Accordingly, in preferred embodiments, the continuous
analyte detection system includes a continuous analyte sensor
(e.g., described elsewhere herein) and a reference analyte sensor.
The continuous analyte sensor is configured to detect a first
signal associated with a test analyte and a second signal is
associated with a reference analyte. The reference sensor is
configured to generate a reference signal associated with the
reference analyte. The test analyte can be any analyte that the
sensor is configured to continuously monitor in the host. For
example, in some preferred embodiments, the test analyte is
glucose. The reference analyte is an analyte other than the test
analyte, which is substantially stable within the host. For
example, in general, the concentration of the reference analyte
(e.g., in the host's circulatory system) does not fluctuate
rapidly. In some preferred embodiments, the reference analyte is
oxygen (O.sub.2); however, a variety of other analytes can be used.
The reference analyte selected is an analyte that can be measured
by both the continuous analyte sensor and the reference sensor.
[0792] The continuous analyte sensor can be any type of continuous
analyte sensor, including a continuous analyte sensor having a
single working electrode or dual-working electrodes. In some
embodiments, the continuous analyte sensor is a single working
electrode continuous analyte sensor configured to detect glucose,
and the first signal is associated with glucose. In this
embodiment, the working electrode is configured to detect the
second signal (associated with the reference analyte). For example,
in some embodiments, the sensor is configured to generate a signal
associated with glucose when a +0.6 mV potential is applied to the
sensor. In some circumstances, the sensor can detect another
analyte, if a different potential is applied thereto. For example,
if a -0.6 mV potential is applied, the sensor can detect O.sub.2.
Accordingly, in some embodiment, the system is configured to detect
both glucose and O.sub.2 (e.g., first and second signals) at the
working electrode of the continuous analyte sensor, by switching
the potential applied to the sensor. In some embodiments, the
continuous analyte sensor includes an auxiliary electrode, which
can be configured to detect the reference analyte (second signal),
as described herein with reference to "transport-measuring"
electrodes.
[0793] In other embodiments, the continuous analyte sensor is a
dual-working electrode continuous analyte sensor configured to
detect glucose, and the first signal (detected by the working
electrode disposed beneath an enzymatic portion of the membrane) is
associated with glucose. In some embodiments, the system is
configured to detect the second signal (associated with the
reference analyte) using the dual-electrode sensor's first working
electrode (E1, with enzyme) as described above. In other
embodiments, the system is configured to detect the second signal
(reference analyte) using the dual-electrode sensors second working
electrode (E2, no enzyme), such as by applying a -0.6 mV potential
thereto. In this embodiment, the second signal associated with the
reference analyte should not be confused with the signal detected
by the second working electrode that is associated with
non-analyte-related electroactive species that have an
oxidation/reduction potential that substantially overlaps with the
analyte's oxidation/reduction potential. For example, in some
embodiments, the dual-electrode sensor is configured such that when
a +0.6 mV potential is applied to the second working electrode (E2,
disposed beneath a non-enzymatic portion of the membrane) the
signal generated is associated with the non-analyte-related
electroactive species that have an oxidation/reduction potential
that substantially overlaps with the analyte's oxidation/reduction
potential; then, when a -0.6 mV potential is applied to the second
working electrode, the second working electrode detects the second
signal (associated with the reference analyte).
[0794] In some embodiments, the continuous analyte sensor includes
more than two working electrodes disposed beneath the membrane. In
one exemplary embodiment, the sensor includes a first working
electrode E1 configured to generate a signal associated with the
analyte (the first signal), a second working electrode E2
configured to generate a second signal associated with the
reference analyte, and a third working electrode E3 configured to
generate a signal associated with the non-analyte-related
electroactive species that have an oxidation/reduction potential
that substantially overlaps with the analyte's oxidation/reduction
potential. In some embodiments, the sensor can include an
additional working electrode (e.g., E4, En) configured to detect
another reference analyte and/or to generate signals associated
with non-analyte-related species that have oxidation/reduction
potentials that overlap with that of another analyte, the reference
analyte, another reference analyte, and the like.
[0795] In preferred embodiments, the reference sensor is not
disposed beneath the analyte sensor's membrane and is configured to
detect the reference analyte using any means known in the art, such
as but not limited to electrochemical, enzymatic, chemical,
physical, immunochemical, radiometric, and the like. In some
preferred embodiments, the reference sensor is an optical sensing
apparatus configured to detect the reference analyte. For example,
the reference sensor can be an optical O.sub.2 sensing apparatus
configured to use one of a variety of optical detection methods
known in the art and a described herein in the section entitled
"Optical Detection."
[0796] In preferred embodiments, the system is configured such that
the continuous analyte sensor and the reference sensor are disposed
in the same local environment and are therefore simultaneously
exposed to (e.g., contacted by/with) the sample (e.g., blood). For
example, in some embodiments, the system can be configured such
that the continuous analyte sensor is a wire sensor configured to
extend into a catheter, and the reference sensor comprises an
optical fiber that is configured both to detect the reference
analyte and to extend into a catheter such that the detecting
portion of the reference sensor is adjacent to the sensing portion
of the continuous analyte sensor. In another exemplary embodiment,
the continuous analyte sensor and the reference sensor are disposed
within a connector; such as described in the section entitled
"Multi-sensor apparatus." In still another exemplary embodiment,
the continuous analyte sensor and the reference sensor are
integrally formed on a vascular access device, such as on the in
vivo portion of a catheter. For example, an optical fiber can be
incorporated into the in vivo portion of the catheter during
manufacture (e.g., such as via injection molding techniques known
in the art) or by attaching the optical fiber with an adhesive, and
subsequent the deposition of the continuous analyte sensor
electrodes to the exterior surface of the in vivo portion of the
catheter, as described herein.
[0797] In preferred embodiments, the system includes a processor
module configured to and/or comprises programming that processes
the second signal (associated with the reference analyte) and the
reference signal to calibrate the first signal (associated with the
analyte). For example, in some embodiments, the processor module
uses the reference signal, which is generated by a sensor outside
the membrane, to calibrate the second signal (generated under the
membrane). Accordingly, shifts in baseline and/or sensitivity,
which can arise over time during use of the sensor, are accounted
for prior to calibration of the first signal (generated under the
membrane). The processor configured to then calibrate the first
signal (analyte signal) using the calibrated second signal, which
generates a first signal substantially without a non-analyte signal
component (and substantially unaffected by shifts in sensitivity
(m) and/or baseline (b)).
[0798] As a non-limiting example, in one embodiment, the system
includes a continuous glucose sensor configured to detect a first
signal associated with glucose and a second signal associated with
O.sub.2. The system also includes an optical sensing apparatus
configured to detect O.sub.2. The system is configured such that
the glucose sensor and the optical O.sub.2 sensing apparatus can be
exposed simultaneously to a sample. This method for calibration
requires measurement of a second analyte that is already being
monitored. For example, optical sensors are almost always used to
measure O.sub.2 in the host. In some embodiments, the glucose
sensor's first working electrode generates both the analyte signal
and the O.sub.2 signal. In some embodiments, an electrode other
than the first working electrode (e.g., a second or third working
electrode) is configured to generate the O.sub.2 signal. Then the
optical O.sub.2 sensor can be used to calibrate the O.sub.2
electrode (of glucose sensor system). Assuming there is a known
relationship between the sensitivities of an electrode configured
to generate a glucose signal and an electrode configured to
generate an O.sub.2 signal, then the sensor's glucose electrode can
be calibrated by the O.sub.2 electrode.
[0799] While not wishing to be bound by theory, it is believed that
an analyte detection system configured to calibrate the analyte
signal using a second/reference analyte provides a plurality of
advantages. Primarily, calibration of a system of the preferred
embodiments does not require input (manually or automatically) of
reference data points from a secondary detection system (e.g.,
separate from the analyte detection system), such as a hand-held
glucose meter. Similarly, no special IV bag, mechanical components
or dedicated IV lines are required. A wide variety of analytes can
be detected by both electrochemical means and a secondary means,
such as optical detection methods. All of these advantages conflate
to provide highly accurate, "plug-and-play" style continuous
analyte detection system that is usable in a wide variety of
settings.
Integrated Sensor System
[0800] System Overview
[0801] In the hospital environment, such as in Intensive Care
Units, patients commonly have multiple access points to their
circulatory systems, for drug and fluid infusion, and for each
blood sample collection. In such settings, a variety of analytes in
the host's blood are regularly monitored, by collection of a blood
sample and sending the sample to an on-site laboratory for
analysis. This system had serious drawbacks, such as giving slow,
non-continuous analyte monitoring results and requiring a lot of
hospital staff attention. For example, tight control of glucose
levels is critical to patient outcome in a critical care medical
setting, especially for diabetic hosts. Maintaining tight glucose
control with current technology poses an undue burden to medical
personnel, due to time constraints and the extensive patient
contact required. Reducing medical staff workload is a key
component of improving patient care in this setting. The preferred
embodiments disclose systems and methods to automatically and
continuously test host analytes at the bedside while reducing
and/or minimizing staff-patient interactions. Additionally, the
preferred embodiments decrease testing intervals and improve sensor
accuracy and reliability.
[0802] FIGS. 6 and 7 illustrate one preferred embodiment of the
integrated sensor system 600 (e.g., for use at the bedside), which
couples to the analyte sensor 14 (e.g., a glucose sensor) and
vascular access device 12 (e.g., a catheter placed in a peripheral
vein or artery) described above (see FIGS. 1A-1E), and which
includes at least one fluid reservoir 602 (e.g., a bag of
calibration or IV hydration solution), a flow control device 604
(e.g., to control delivery of an infusion fluid 602a from the
reservoir to the host via the catheter), a local analyzer 608 and a
remote analyzer 610. In some embodiments, the analyte sensor is
configured to reside within the catheter lumen 12a (see FIGS.
1A-1E). In some embodiments, the sensor is disposed within the
catheter such the sensor does not protrude from the catheter
orifice 12b. In other embodiments, the sensor is disposed within
the catheter such that at least a portion of the sensor protrudes
from the catheter orifice. In still other embodiments, the sensor
is configured to move between protruding and non-protruding
configurations. The analyte sensor and vascular access device used
in the integrated sensor system 600 can be any types known in the
art, such as but not limited to analyte sensors and vascular access
devices described above, in the sections entitled
"Applications/Uses" and "Exemplary Sensor Configurations." For
convenience, the vascular access device 12 will be referred to as a
catheter herein. However, one skilled in the art appreciates that
other vascular access devices can be used in place of a
catheter.
[0803] In some embodiments, at least one electronics module (not
shown) is included in the local and/or remote analyzers 608, 610
respectively, for controlling execution of various system
functions, such as but not limited to system initiation, sensor
calibration, movement of the flow control device 604 from one
position to another, collecting and/or analyzing data, and the
like. In preferred embodiments, the components and functions of the
electronics module can be divided into two or more parts, such as
between the local analyzer and remote analyzer, as is discussed in
greater detail in the sections entitled "Local Analyzer" and
"Remote Analyzer."
[0804] In some embodiments, the flow control device 604 includes
one or more valves and is configured to control fluid delivery to
the host and sample take-up (e.g., drawing blood back into the
catheter until at least the sensor's electroactive surfaces are
contacted by the blood). In some embodiments, the sensor 14 dwells
within the lumen 12a of the catheter 12, as described elsewhere
herein. In some embodiments, wherein an internal calibration is
performed, an infusion fluid (e.g., calibration solution 602a)
flows over the indwelling sensor 14 and is infused into the host.
Generally, analyte in the solution 602a can be measured when the
sensor electroactive surfaces are in contact with the solution
602a. In some embodiments, the measurements of the solution 602a
can be used to calibrate the sensor 14. After calibration, the
system is configured such that a sample (e.g., blood or other
bodily fluid) contacts the sensor's electroactive surfaces (e.g.,
by drawing blood back into the catheter). When the sample contacts
the electroactive surfaces, the sample's analyte concentration can
be detected by the sensor 14. When a sample is drawn back, the
sample can then be returned to the host. In some embodiments, the
integrated sensor system 600 cycles between calibration (e.g.,
measurement of a reference calibration solution) and measurement
(e.g., of a sample, such as blood, glucose concentration). In some
embodiments, the system 600 continues operation in this cyclical
manner, until the system 600 is either disconnected from the host
or turned off for a period of time (e.g., during movement of the
host from one location to another). For example, in one embodiment,
the system 600 cycles between the calibration and measurement steps
from about every 30 seconds or less to about every 2 hours or more.
In another embodiment, the system 600 cycles between the
calibration and measurement steps of from about every 2 minutes to
about every 45 minutes. In still another embodiment, the system 600
cycles between the calibration and measurement steps from about
every 1 minute to about every 10 minutes. In some embodiments, the
user can adjust the time between steps. In some embodiments, the
user can adjust the time between each step. In some embodiments,
the system 600 can perform additional steps, such as but not
limited to a flushing step, a keep vein open step (KVO), an
extended infusion step, and the like. In some embodiments, the time
is dependent upon sensors that detect a reference solution (e.g.,
calibration solution) and/or sample (e.g., blood) at the
electroactive surfaces.
[0805] The integrated sensor system 600 of the preferred
embodiments provides several advantages over prior art technology.
Namely, in preferred embodiments, continuous analyte monitoring is
enabled. When the analyte is glucose, continuous glucose monitoring
enables tight glucose control, which can lead to reduced morbidity
and mortality among diabetic hosts. Additionally, the medial staff
is not unduly burdened by additional patient interaction
requirements. Advantageously, there is no net sample (e.g., blood)
loss for the host, which is a critical feature in some clinical
settings. For example, in a neonatal intensive care unit, the host
is extremely small and loss of even a few milliliters of blood can
be life threatening. Furthermore, returning the body fluid sample
to the host, instead of delivering to a waste container greatly
reduces the accumulation of biohazardous waste that requires
special disposal procedures. The integrated sensor system
components, as well as their use in conjunction with an indwelling
analyte sensor, are discussed in greater detail below. Fluids
[0806] Referring to FIGS. 6 and 7, in preferred embodiments, the
integrated sensor system 600 includes at least one reservoir 602
that contains an infusion fluid 602a, such as but not limited to
reference (e.g., calibration), hydration and/or flushing solutions.
For simplicity, the infusion fluid 602a will be referred to herein
as a solution 602a. However, one skilled in the art recognizes that
a wide variety of infusible fluids can be used in the embodiments
discussed herein.
[0807] In some embodiments, the reservoir 602 includes a container
such as but not limited to an IV bag. In other embodiments, the
reservoir 602 can include two or more IV bags, or any other sterile
infusion fluid container. In some embodiments, the reservoir 602 is
a multi-compartment container, such as but not limited to a
multi-compartment IV bag. If two or more solutions 602a (e.g.,
calibration solutions, flush solutions, medication delivery
solutions, etc.) are used, the solutions 602a can be contained in
two or more IV bags or in a multi-compartment IV bag, for example.
In some embodiments, it is preferred to use a single solution 602a.
Use of a single solution 602a for calibration, catheter flushing
and the like simplifies the system 600 by reducing the complexity
and/or number of system 600 components required for system 600
function. In some embodiments, two or more solutions 602a are
preferred, and can be provided by a multi-compartment IV bag or two
or more separate reservoirs 602 (e.g., two or more bags, each
containing a different solution 602a). Advantageously, use of
multiple solutions 602a can increase system functionality 600 and
can improve sensor accuracy.
[0808] Any infusion fluid (e.g., solution 602a) known in the art
can be used in conjunction with the present system 600. In some
embodiments, the solution 602a is an analyte-containing solution
that can be used as a reference or standard for sensor 14
calibration (generally referred to as a reference and/or
calibration solution in the art). In some embodiments, a solution
602a can be used as a flushing solution, to wash a sample off the
sensor 14 and out of the catheter 12. In some embodiments, two or
more solutions 602a (e.g., having different analyte concentrations)
can used to provide two or more calibration measurements. In one
exemplary embodiment, the analyte sensor 14 is a glucose sensor,
and the solution 602a contains dextrose or glucose at a
concentration of from about 0 mg/dl to about 400 mg/dl. In
preferred embodiments, the solution 602a contains from about 75
mg/dl to about 200 mg/dl glucose. In more preferred embodiments,
the solution 602a contains from about 100 mg/dl to about 150 mg/dl
glucose. In some embodiments, the solution 602a is an isotonic
saline solution. In some embodiments, the solution 602a contains a
sufficient concentration of an anticoagulant to substantially
prevent blood clotting in and/or near the catheter 14. In some
embodiments, the solution 602a contains a sufficient concentration
of or antimicrobial to substantially prevent infection in and/or
near the catheter. In one exemplary embodiment, the reservoir 602
is a 500 ml bag containing a sterile solution 602a including 0.9%
sodium chloride in water (e.g., normal saline), 2 IU/ml heparin and
100 mg/dl dextrose. In another exemplary embodiment, the reservoir
602 is a 500 ml bag containing heparinized saline.
[0809] In some embodiments, one, two or more solutions 602a can be
used in conjunction with the integrated sensor system 600. For
example, in some embodiments, two or more calibration solutions
602a (e.g., solutions with different analyte concentrations) can be
used. In one preferred embodiment, the analyte sensor 14 is a
glucose sensor and the calibration solution 602a includes a glucose
concentration of from 0 mg/dl to about 300 mg/dl or more. In one
exemplary embodiment, a single calibration solution 602a (e.g.,
having a 100 mg/dl glucose concentration) can be used. In another
exemplary embodiment, two calibration solutions 602a (e.g., having
100 mg/dl and 0 mg/dl glucose concentrations) can be used. In other
exemplary embodiments, three calibration (e.g., 0 mg/dl glucose, 75
mg/dl glucose and 300 mg/dl glucose) solutions 602a can be used. In
still other embodiments, more than three calibration solutions 602a
can be used. In addition to calibration solutions 602a,
non-calibration solutions 602a can be used in conjunction with the
integrated sensor system 600, such as but not limited to
intravenously administered drugs, insulin, enzymes, nutritional
fluids, and the like.
[0810] In some circumstances, it is preferred to infuse two or more
different solutions (e.g., provided in separate IV bags) to the
host through the same IV tubing, while not mixing the solutions in
the tubing. In some embodiments, the system is configured to infuse
two or more separate solutions without mixing by inserting (e.g.,
injecting) a small oxygen bubble between the two different
solutions as they are released from the IV bags (e.g., when
switching from one solution to the other). In some embodiments,
alternative gases or a small amount of glycerin is substituted for
oxygen. The size of the bubble necessary to separate the two fluids
depends in part on the inner diameter of the tubing. For example, a
smaller bubble is required when smaller internal diameter tubing is
used than when larger internal diameter tubing is used. In some
embodiments, the bubble has a volume of from about 1, 3, 5-.mu.l to
about 6, 8, 10, 15, 20, 25 or 30 .mu.l or greater. In some
embodiments, the bubble is injected at the flow control device. In
some embodiments, the system includes a bubble injector.
[0811] The solution 602a can be provided to the user in a variety
of ways, depending upon local hospital protocol and/or physician
preference. In some embodiments, the solution 602a is supplied
pre-mixed (e.g., an IV bag containing sodium chloride, dextrose and
heparin), such that fluid reservoir 602 can be connected to an
infusion set and infused into the host with minimal effort. In
other embodiments, one or more of the solution components 602a can
be provided separately, such that the final solution 602a is
prepared at the host's bedside, at the nurse's station or in the
hospital pharmacy, for example. In one exemplary embodiment, the
solution 602a can be provided to the medical staff as a kit
including a bag of sterile solution (e.g., water) and injectable
sodium chloride, dextrose and heparin aliquots of sufficient
quantity to prepare the final solution 602a. The solution 602a can
be mixed at the bedside or at a location remote from the host, and
then applied to the host and to the integrated sensor system 600.
In some embodiments, the reservoir 602 is a 500 ml or 1000 ml bag
containing a sterile solution of heparinized saline and 100 mg/dl,
150 mg/dl or 200 mg/dl glucose.
[0812] In various preferred embodiments, the solutions 602a are
administered with standard IV administration lines, such as those
commonly used today, such as a sterile, single-use IV set, referred
to herein as tubing 606. In some embodiments, the tubing 606 can be
provided with the solution(s) 602a. While in other embodiments, the
tubing 606 can be provided separately from the solution(s) 602a or
other system components. Additional system 600 components that can
be provided with the solution(s) 602a include but are not limited
to a sensor 14, a catheter 12, tubing 606, a local analyzer 608,
wires and/or cables for hardwire connections between system
components, and the like.
[0813] In some embodiments, multiple solutions 602a can be infused
through a multi-lumen catheter 12, such as but not limited to a
two-lumen or three-lumen catheter. In some embodiments, the sensor
14 is disposed in one of the catheter's lumens 12a, through which
one or more calibration solutions 602a can be passed, while other
fluids (e.g., hydration fluids, drugs, nutritional fluids) to be
delivered to the patient are infused through the other catheter 12
lumens 12a (e.g., second, third or more lumens).
[0814] In some embodiments, the reservoir 602 is held by a support
612. The support 612 can take many forms, such as an elevated
support. In some embodiments, the support 612 is an IV pole, such
those commonly used in medical care facilities. In some
embodiments, the reservoir 602 is suspended on the support 612, and
the height of the reservoir 602 can be adjusted (e.g., raised or
lowered) to modulate solution 602a discharge from the reservoir
602.
[0815] In some embodiments, the reservoir 602 and solution 602a can
be provided with one or more system 600 components, such as in a
kit. In one exemplary embodiment, a kit including the components to
mix the solution 602a can include an analyte sensor 14 and a
standard infusion set (e.g., catheter 12, cannula, IV tubing 606,
etc.). In other embodiments, a kit can include a premixed solution
602a, with an analyte sensor 14. In various embodiments, a kit can
contain instructions for use, such as for mixing the solution 602a
and applying it to the integrated sensor system 600.
Advantageously, providing either a pre-mixed solution 602a or
solution components with one or more system 600 components (e.g.,
sensor 14, catheter 12, tubing 606, local analyzer 608) can
increase efficiency of medical care and provide ease of use to the
nursing staff.
[0816] Flow Regulators
[0817] Still referring to FIGS. 6 and 7, in some embodiments, a
flow regulator 602b controls the solution 602a flow rate from the
reservoir 602 to the flow control device 604, which is described
below. A variety of flow regulators can be used with the preferred
embodiments, including but not limited to pinch valves, such as
rotating pinch valves and linear pinch valves, cams and the like.
In one exemplary embodiment, the flow regulator 602b is a pinch
valve, supplied with the IV set and located on the tubing 606
adjacent to and below the drip chamber. In some embodiments, a flow
regulator 602b controls the flow rate from the reservoir 602 to a
flow control device 604, which is described in the section entitled
"Flow Control Device." In some embodiments, a flow regulator is
optional; and a flow control device 604 controls the flow rate
(e.g., from the reservoir 602 to the catheter 14, described
elsewhere herein).
[0818] Flow Control Device
[0819] In preferred embodiments, the integrated sensor system 600
includes a flow control device 604. In some embodiments, the flow
control device 604 is configured to regulate the exposure of the
sensor 14 to the solution 602a and to host sample (e.g., blood or
other bodily fluid). In some embodiments, the flow control device
604 can include a variety of flow regulating devices, such as but
not limited to valves, cams, pumps, and the like. In one exemplary
embodiment, the flow control device 604 includes a simple linear
pinch valve. In another exemplary embodiment, the flow control
device 604 includes two or more linear pinch valves. In another
exemplary embodiment, the flow control device 604 includes one or
more non-linear pinch valves. In another exemplary embodiment, the
flow control device 604 includes a global valve. In still another
exemplary embodiment, the flow control device 604 includes a gate
valve, such as but not limited to a rising stem or non-rising-stem
valve. In another exemplary embodiment, the flow control device 604
includes a butterfly valve or a ball valve. In still another
exemplary embodiment, the flow control device 604 includes a pump,
such as but not limited to volumetric infusion pumps, peristaltic
pumps, piston pumps and syringe pumps. In still other exemplary
embodiments, the flow control device 604 can be configured to vary
the pressure at the reservoir 602, such as but not limited to a
pressure cuff around an IV bag and/or raising/lowering the
reservoir adjust head pressure. In some embodiments, the flow
control device 604 includes a gravity-fed valve. In still other
embodiments, the flow control device 604 is configured to use flow
dynamics at the catheter 12, to regulate exposure to the sensor to
solution or sample, as described elsewhere herein. Although some
exemplary glucose sensors are described in detail herein, the
system 600 can be configured to utilize a variety of analyte
sensors including a variety of measurement technologies, such as
enzymatic, chemical, physical, electrochemical, spectrophotometric,
polarimetric, calorimetric, radiometric, and the like.
[0820] Referring now to a preferred embodiment wherein the sensor
is an enzyme-based sensor, it is known to those skilled in the art
that the rate of an enzymatic reaction is temperature dependent.
Depending upon the enzyme, temperature reductions generally slow
enzymatic reaction rates; temperature increases generally increase
reaction rates. Since the analyte sensors 14 described in the
preferred embodiment herein depend upon an enzyme (e.g., GOX) to
detect the analyte (e.g., glucose) temperature changes during
sensor calibration can result in artifacts on the sensor signal.
For example, if the solution 602a temperature is reduced (relative
to body temperature), the enzymatic reaction will proceed at a
reduced rate (relative to the rate at body temperature), causing
the solution's analyte concentration to appear artificially low,
which can result in improper sensor calibration. In some
circumstances, changes in the relative temperatures of the area of
the host's body surrounding the sensor (e.g., the blood contacting
the sensor and the flesh surrounding the implanted sensor) and of
the solution 602a can be caused by the host moving the implant
site, covering (or uncovering) an implant site with a blanket,
application of a heating pad or ice to the implant site, and the
like. In some circumstances, a high flow rate can cause large
temperature fluctuations when the sensor is alternately exposed to
blood and solution 602a. For example, if the flow rate is
sufficiently slow, the infusion fluid 602a can be sufficiently
warmed by the body before it contacts the sensor; thus the
calibration measurements taken will be made at a temperature
substantially similar to the temperature with the test measurements
are taken in blood. If the flow rate is too fast, the infusion
fluid 602a will not warm up sufficiently, and the temperature will
be too cold when the calibration measurements are taken, which can
lead to improper sensor calibration. An improperly calibrated
sensor can aberrantly measure the analyte concentration in the
sample (e.g., blood from the host). Aberrant readings of sample
analyte concentration can lead to improper treatment decisions by
the medical staff and/or the host. The effects of temperature on
enzymatic reaction rates can be mathematically described using a
temperature coefficient. Signal artifacts caused by
temperature-related reductions in enzyme reaction rate are referred
to herein as temperature coefficient artifacts.
[0821] Generally, the host tissue in which the catheter 12 has been
implanted surrounds an in vivo portion of the catheter 12. In
preferred embodiments, the flow control device 604 is configured to
pass the solution 602a through the catheter 12 at a rate such that
the solution's temperature substantially equilibrates with the
temperature of the surrounding host tissue. In one exemplary
embodiment, the flow control device 604 maintains a flow rate of
from about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08,
0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007,
0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/min or less to about
1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or
more. In one exemplary embodiment, the flow rate is from about 0.5
.mu.l/min or less to about 1.5 ml/min or more. In one preferred
embodiment, the flow rate is from about 1 .mu.l/min to about 1.0
ml/min. In one exemplary preferred embodiment, the flow rate is
from about 0.01 ml/min to about 0.2 ml/min. In another exemplary
preferred embodiment, the flow rate is from about 0.05 ml/min to
about 0.1 ml/min. Advantageously, since the flow control device 604
infuses the solution 602a at a rate sufficient to allow substantial
temperature equilibration with the surrounding tissue, sensor 14
accuracy is improved and the integrated sensor system 600 has
substantially no temperature coefficient artifacts.
[0822] In some alternative embodiments, a faster flow rate that
does not allow for temperature equilibration is preferred. In such
circumstances, measurement inaccuracies due to temperature
coefficient can be generally eliminated mathematically using
b.sub.offset and the calibration methods described in the section
entitled "Systems and Methods for Processing Sensor Data."
[0823] In some embodiments, sample is taken up into the same
catheter lumen 12a through which the solution 602a is infused into
the host (described elsewhere herein). Thus, it is preferred that
mixing of the sample and the solution 602a is prevented. Similarly,
it can be advantageous to detect when the sensor 14 is in contact
with undiluted sample and/or undiluted solution. In some preferred
embodiments of the integrated sensor system 600, the flow control
device 604 is configured to substantially prevent mixing of two or
more fluids, such as but not limited to the solution 602a and a
host sample (e.g., blood). In preferred embodiments, mixing can be
substantially prevented by a combination of factors, including
specific gravity and flow rate. It is known that two solutions with
different specific gravities tend not to mix, provided that the
fluids are moved at a sufficiently slow rate (e.g., flow rate).
Human whole blood has a specific gravity of about 1.05-1.06, while
an infusion solution of 5% dextrose and 0.225% NaCl has a specific
gravity of about 1.0189. Due to the difference in specific
gravities, a blood sample and the solution 602a tend to resist
mixing within the tubing 606 when the flow rate is sufficiently
slow. In preferred embodiments, the sample and the solution 602a
are moved within the catheter lumen 12a at a rate such that
substantially no mixing occurs therebetween. In some embodiments,
the flow rate is from about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2,
0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009,
0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/min or
less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or
2.0 ml/min or more. In some embodiments, the flow rate is from
about 0.01 ml/min to about 1.0 ml/min. In one exemplary embodiment,
the flow rate is from about 0.02 ml/min to about 0.35 ml/min. In
another exemplary embodiment, the flow rate is from about 0.02
ml/min to about 0.2 ml/min. In yet another exemplary embodiment,
the flow rate is from about 0.085 ml/min to about 0.2 ml/min.
[0824] In preferred embodiments, the flow control device 604 can
include a variety of fluid flow-regulating devices known in the
art. In some embodiments, the flow control device 604 includes one
or more valves, such as but not limited to linear and non-linear
roller valves, linear and non-linear pinch valves, bi-directional
valves (either linear or non-linear), peristaltic rollers, cams,
combinations thereof, and the like. In some other embodiments, the
flow control device 604 is configured to generate sufficient "head
pressure" to overcome the host's blood pressure such that the
solution 602a is infused into the host at a controlled rate; this
can include elevating the fluid reservoir 602 (e.g., gravity fed)
and using a valve to control the fluid flow rate out of the
reservoir 602 and into the host. In one exemplary embodiment, the
fluid flows at a maximum rate (e.g., about 6.25 ml/hr, 0.1 ml/min)
such that a maximum fluid volume of about 150 ml/day can be infused
into the host, however ranges much higher and/or lower can be
implemented with the preferred embodiments.
[0825] In one exemplary embodiment, the flow control device 604 is
a rotating pinch valve that has first and second positions. The
valve can move between the two positions, for example, backward and
forward, and thereby move fluids in and out of the catheter, as
described in the section entitled "Flow Control Device Function."
Namely, solution 602a can be moved from the reservoir 602, over the
electroactive surfaces of the sensor 14 and into the host; and
sample can be drawn up from the host, to cover the electroactive
surfaces of the sensor 14, and then pushed back into the host, by
movement of the valve between the first and second positions.
[0826] In one exemplary embodiment, the flow control device
includes a rotating pinch valve as described with reference to
FIGS. 8A through 8C. Although FIGS. 8A to 8C describe one
implementation of a rotating pinch valve that can be implemented
with the sensor system, some alternatives include rotating pinch
valves with multiple pinch surfaces, for example around the
circumference of the rotatable axle (FIGS. 8A-8C, 804), which
enables the use of one valve for multiple infusion fluids (e.g.,
using multiple IV lines).
[0827] In some embodiments, the flow control device 604 includes
one or more cams that regulate the flow rate. In one embodiment,
the flow control device 604 includes a plurality of fixed orifices,
which are opened and closed by the cams. As the cams are rotated,
the flow increases and/or decreases in response. In one exemplary
embodiment, the flow control device 604 includes three openings and
three cams that mate with the openings (one cam per opening); fluid
can flow through each opening at a given rate, X ml/min.
Accordingly, when the cams close all three openings, flow is
stopped. When one of the openings is opened, the fluid flows at X
ml/min. If two openings are opened, fluid flows at 2.times.ml/min.
Similarly, when the three openings are opened (e.g., by turning the
cams such that they no longer close the openings), the fluid flows
at 3.times.ml/min.
[0828] In another example, the flow control device 604 includes a
plurality of cams and an equal plurality to tubes 606 passing
through the cams, such that each cam can pinch closed the tube 606
that passes through it. In an exemplary embodiment, the cams are
arranged such that they pinch and roll the tubing 606, such that
fluid is pushed into the host and sample taken up at pre-determined
rates and times. For example, the flow control device 604 can
include two cams, each having a tube 606 threaded therethrough. The
cams are arranged such that each cam pinches and rolls the tubing
606 passing therethrough to push fluid into the host at one or more
rates and to take up a blood sample.
[0829] In yet another example, the flow control device includes a
rotating ball valve controlled by a motor, wherein the direction of
the ball valve can be utilized to control a variety of functions,
such as flow direction of the fluid.
[0830] As described in related herein, the sensor can be calibrated
using more than one reference/calibration solution. For example, in
some embodiments, the system is configured to calibrate using two
reference solutions. In some embodiments, two solutions are used by
metering the flow of one solution with the flow control device and
intermittently stopping and intermittently manually injecting the
second solution such that the solution contacts the sensor a
sufficient period of time for calibration measurements to be taken.
However, in preferred embodiments, the flow control device is
configured to automate such "intermittent" calibrations (e.g.,
instead of manually injecting the calibration solution into the
tubing) by actuating a secondary valve in a time-dependent manner,
wherein the secondary valve in configured to meter the second
calibration solution. The secondary valve can take on a variety of
configurations, such as but not limited to a pinch valve, a ratchet
valve, a cam, locking bearings or a ball valve (within the
tubing).
[0831] As a non-limiting example, the secondary valve is a pinch
valve that includes a ratcheting disk attached to the front of the
flow control valve (e.g., via an axle), first and second arms, and
includes a pin that can engage the tip of the second arm. In some
preferred embodiments, the first and second arms are connected to
each other by a joint, which includes a biasing means, such as a
torsional spring, that pushes the second arm toward the ratcheting
disk. The joint includes a stop pin, which limits the distance the
second arm can move away from the ratcheting disk. The first arm
includes a detent (e.g., a finger) that is pressed into the tubing
(threaded through the flow control device) by another biasing means
configured to push the first arm toward the ratcheting disk.
Accordingly, in some embodiments, when the flow control device
rotates in the first direction the ratcheting disk is not engaged,
and the first arm pinches the tube closed. In other embodiments,
when the flow control device rotates in the first direction, the
disk rotates with the flow control device such that the tip of the
second arm rides up and over the pin of the secondary valve. When
the flow control device rotates in the second direction, it is
configured to engage the ratcheting disk and has two positions. As
the flow control device rotates to the first position, blood is
taken up into the catheter. At this point, the flow control device
is configured to reverse and rotate in the first direction.
However, a portion of the time, the flow control device rotates to
the second position. As the flow control device rotates to the
second position, the ratcheting disk remains engaged and the disk
rotates far enough that the pin (on the disk) engages the tip of
the second arm. Accordingly, the second arm is pushed away from the
flow control device. The continued movement of the second arm is
prevented by the stop pin. Since the second arm must continue to
move away from the flow control device/ratcheting disk, the first
arm is engaged by the second arm, and the entire structure is
pushed away from the flow control device. Accordingly, the pinch on
the tubing (e.g., by the detent) is relieved and the fluid in the
tubing can flow. After a desired amount of fluid has flowed through
the tubing, the pinch of the tubing (by the detent) is reapplied,
by moving the flow control device/ratcheting disk in the first
direction.
[0832] As another non-limiting example, in some embodiments the
flow control device includes a cam configured to control the
pinching and un-pinching of the tubing. For example, a cam (e.g.,
weighted) is attached to the flow control device or another
structure (e.g., a ratcheting disk) attached to the flow control
device. The tubing is compressed (pinched) by a detent on an arm.
The arm has a joint and is biased towards the flow control device
via a biasing means. At desired time points, the flow control
device is configured to move the cam to a second position (e.g.,
180.degree.), such that the arm is pushed upward (e.g., by the cam)
and the pinch of the tubing is relieved. When the pinch of the
tubing is relieved, the solution can flow through the tubing. The
flow control device then returns the cam to its first position, so
that the tubing is recompressed (pinched) and fluid flow is
stopped.
[0833] In some embodiments, an electronics module (not shown) is
incorporated into the flow control device 604, to provide local
control over flow control device function; in these embodiments,
the flow control device function can be transmitted to the local
and/or remote analyzer for processing. In other embodiments, a
remote analyzer 610 and/or electronics module, such as but not
limited to a computer system, controls the flow control device 604.
System 600 components that regulate the flow control device 604 are
discussed in greater detail elsewhere herein.
[0834] In a further embodiment, the flow control device 604 is a
computer controlled rolling pinch valve that acts on the exterior
of sterile tubing 606 in order to control the flow rate of a
solution 602a from an elevated fluid reservoir 602 into the host.
In preferred embodiments, the flow control device 604 is configured
to pinch and roll a small volume of tubing 606 such that a sample
of host blood is drawn up into the catheter 12 (e.g., with a sensor
14 disposed therein) for analyte measurement, and to then push the
sample back into the host with a solution (e.g., the calibration
solution 602a). In general, the flow control device 604 is
configured to oscillate between drawing up a blood sample and
allowing flow of the calibration solution 602a at a predetermined
rate. In some embodiments, the flow control device 604 includes at
least one "hard stop" that ensures that the flow control device 604
does not move to a position that could endanger and/or injure the
host, such as by draining the IV bag 602 of fluid 602a or
inappropriately (e.g., excessively) withdrawing blood, for
example.
[0835] Tubing and Catheter
[0836] Referring again to FIGS. 6 and 7, in preferred embodiments,
the integrated sensor system 600 includes tubing 606 (e.g., sterile
tubing configured for use in intravascular fluid infusion) and a
catheter 12, to deliver the solution 602a from the reservoir 602 to
the host. Generally, the tubing 606 and catheter 12 are sterile,
single use devices generally used in medical fluid infusion, and
may be referred to as an "infusion set." An infusion set may
include additional components, such as but not limited to a cannula
or needle for implanting the catheter, sterilization fluid (e.g.,
on a gauze pad) for cleaning and/or sterilizing the insertion site
(e.g., the host's skin), tape, gauze, and the like. IV tubing is
available in a variety of sizes and configurations, which find use
in the preferred embodiments. For example, the tubing can be any
size internal diameter, such as from about 0.5 mm to about 5 mm
internal diameter. In various embodiments, the tubing can include a
drip chamber and/or one or more access devices, such as but not
limited to stopcocks, diaphragms and the like.
[0837] Catheters 12 are available in a variety of sizes and
configurations. Catheters 12 for use in conjunction with an analyte
sensor 14 are described in detail, elsewhere herein. Briefly, the
catheter 12 can be any single- or multi-lumen catheter having a
straight or divided tubing connector (e.g., straight-through,
single shut off, double shut off, non-spill couplings, valves,
T-connectors, Y-connectors, X-connectors, pinch clamps, Leur locks,
back-flow valves, and the like). In some embodiment, the catheter
is configured for insertion into the venous side of the host's
circulatory system. In other embodiments, the catheter is
configured for insertion into the arterial side of the host's
circulatory system, into either a peripheral or a central artery.
In some embodiments, the catheter 12 is configured with an
integrally formed sensor 14. In alternative embodiments, a
non-integral sensor 14 is configured for insertion into the
catheter 12 after catheter insertion. In some embodiments, the
catheter 12 is a single lumen catheter that is configured for
infusion of a fluid.
[0838] In another embodiment, the catheter includes at least two
lumens (e.g., a dual-lumen catheter), wherein each lumen includes
an orifice configured and arranged for fluid communication with the
bodily fluid of the host. In some embodiments, the first lumen is
configured for fluid infusion and the second lumen is configured
for insertion of an analyte sensor. In preferred embodiments, the
orifice of the second lumen is located more proximal to the second
end of the catheter (e.g., the catheter hub) than the first lumen
orifice, such that a bodily fluid drawn back into the second lumen
is substantially undiluted by a fluid infused through the first
lumen. Accordingly, a sample substantially undiluted by fluid being
infused into the host can be drawn back for testing by the analyte
sensor located in the second lumen. In this embodiment, the
catheter is no longer a "dedicated line" that is dedicated to the
analyte sensor. In some embodiments, the catheter includes three or
more lumens. During insertion, a cannula or needle can be inserted
into one of the catheter's lumens, such that the catheter is
substantially supported during the insertion process. For example,
in some embodiments, the sensor and dual-lumen catheter can be
provided to the user with a cannula pre-inserted into the first
lumen and the sensor pre-inserted into the second lumen. After
insertion, the cannula is removed (the sensor remains in the second
lumen) and IV tubing is connected to the catheter hub. In some
embodiments, the catheter, such as but not limited to a dual lumen
catheter, is formed from an extruded polymer containing an amount
of Ag and/or AgCl such that the catheter itself functions as a
reference electrode.
[0839] In some preferred embodiments, an indwelling sensor 14 is
disposed within the catheter's lumen 12a. In some embodiments, the
catheter 12 and sensor 14 are provided to a user together. In other
embodiments, the catheter 12 and sensor 14 are supplied separately.
In an alternative embodiment, the catheter 12 is a multi-lumen
catheter configured for infusion of two or more solutions. In
preferred embodiments, a sensor 14 is disposed within one of the
catheter's multiple lumens 12a. For example, a calibration solution
602a (e.g., 100 mg/dl glucose in saline) can be infused through the
lumen 12a in which the sensor 14 is disposed, while a hydration
fluid (e.g., including a medication) can be infused through a
second lumen. Advantageously, a dual lumen catheter 12 allows
non-interrupted system use while other fluids are concurrently
provided to the host.
[0840] In some embodiments, only the working electrode(s) of the
sensor 14 are disposed within the catheter lumen 12a and the
reference electrode is disposed remotely from the working
electrode(s). In other embodiments, the sensor 14 is configured to
intermittently protrude from the catheter lumen 12a.
[0841] Referring now to FIGS. 10A-10D, in some embodiments, the
flow control device and the IV tubing (e.g., the tubing set) are
configured and arranged to releasably mate in a specific
orientation. In some embodiments, the flow control device (e.g.,
the valve 604) and the tubing (referred to herein as a "tubing
assembly" 606a or a tubing set) are configured and arranged for
uni-directional tubing installation (e.g., the tubing can be
installed in only one direction). For example, the tubing assembly
shown in FIGS. 10A-10D includes first and second connector ends
606c, 606d joined by a central portion of tubing 606b. The central
portion of tubing is sufficiently elastic that the tubing assembly
can be stretched during installation into the valve. For example,
the tubing assembly is held by the first and second ends 606c, 606d
during insertion into grove 803 of the valve. After the tubing is
installed in the groove, the first and second ends are released,
allowing the central portion to relax into a less-stretched
configuration. In some embodiments, the valve and/or tubing (e.g.,
the central portion) are configured and arranged such that the
tubing is in a stretched state (e.g., elongated configuration)
after installation. For example, the tubing can be slightly shorter
than the distance from one end of the valve to the other (e.g., the
longitudinal length of the groove). In some embodiments, the
tension created by the remaining stretch in the central portion
helps to hold the tubing assembly in place during valve operation.
Advantageously, uni-directional tubing installation can enable
alignment of tubing components with specific valve components, such
that the aligned tubing and valve components can function together,
such as described in the section entitled "Free Flow
Mitigation."
[0842] In further embodiments, the valve and tubing (e.g., tubing
assembly 606a) are configured and arranged to form a mechanical
interlock when mated. Advantageously, the mechanical interlock can
reinforce and/or enable uni-directional tubing installation and/or
help to maintain the installation of the tubing within the valve
during valve operation. The mechanical interlock includes
releasably engageable first and second portions; namely, the valve
comprises the first portion 809 (described elsewhere herein) of the
mechanical interlock and the tubing assembly comprises the second
portion (e.g., the second end 606d of the tubing assembly 606a) of
the mechanical interlock. For example, in FIGS. 10A and 10B, the
bottom portion 606d of the tubing assembly 606a is configured as a
male connector (e.g., including wings, fins, detents, fingers,
etc.) configured to releasably mate with a female interconnection
809 on the valve. For example, in the embodiment illustrated in
FIG. 10A, the bottom portion 606d of the tubing assembly includes a
male interconnection (e.g., a key) having a rectangular body and an
optional female portion of a Leur connector (e.g., for releasably
mating with the male Leur connector of IV tubing); the valve's
interlocking female interconnection (e.g., a lock) includes a
rectangular receptacle sized to receive the male interconnection,
including a cylindrical indentation (e.g., a concave groove or
well) sized and/or shaped to receive the optional Leur connector of
the bottom portion. As another example, in the embodiment
illustrated in FIG. 10B, the bottom portion 606d of the tubing
assembly includes fins having curved edges. Advantageously, the
mechanical interlock, of the tubing assembly and the valve,
prevents twisting (e.g., rotational movement) of the tubing
assembly within the valve.
[0843] In some embodiments, the configuration of an interconnection
(e.g., the male interconnection of the tubing assembly and/or the
female interconnection of the valve) is associated with a specific
flow profile. For example, a first interconnection configuration is
associated with a first flow profile; a second interconnection
configuration is associated with a second flow profile; and so on.
In a further embodiment, the interconnection and/or flow profile is
associated with a specific system configuration, such as for use in
a specific circumstance. For example, the system can be configured
for uses in pediatric and/or adult hosts. Each type of host has a
set of requirements associated with the system configuration. For
example, a pediatric host is much smaller than an adult host, and
thus may require a smaller catheter/fluid coupler and analyte
sensor and slower infusion relative to an adult host. In some
embodiments, the system is configured to recognize an
interconnection (e.g., the configuration) and to use (e.g.,
program, select) the flow profile associated with the recognized
interconnection. In some embodiments, the interconnection is
mechanical. In other embodiments, the interconnection includes an
electronic component, such as but not limited to an RFID chip
located in the tubing assembly (e.g., in the male interconnection
of the mechanical interlock) that is detected by the flow control
device.
[0844] As is described elsewhere herein, the valve is configured
and arranged for at least two fluid flow positions, namely a
gravity flow (also referred to as free flow) position and a
controlled flow position. For example, in some embodiments, the
valve is configured and arranged such that the tubing is
substantially straight in the gravity flow position and the tubing
is substantially non-linear in the controlled flow position. In
general, the position of the valve, including its direction and
rate of movement, is associated with (e.g., corresponds to) the
flow position, which in turn is associated with (e.g., corresponds
to) a flow rate. FIG. 10C illustrates the gravity flow valve
position, which corresponds to a valve position in which the valve
is substantially open (e.g., the tubing 606b of the tubing assembly
is not substantially pinched), such that the infusion fluid can
flow freely through the valve. In some embodiments, the gravity
flow position comprises a flow rate of at least about 600 ml/hr
(e.g., 10-ml/min). In contrast, the controlled flow position (e.g.,
FIG. 10D) includes a pinch 808 in the tubing 606b and movement of
the pinch in the tubing (e.g., by the valve), such that the rate of
fluid flow (e.g., including flow direction) is controlled by the
valve. In some embodiments, the controlled flow position provides a
flow rate of from about 0.001, 0.002, 0.003, 0.003, 0.004, 0.005,
0.006, 0.007, 0.008 or 0.009-ml/min or less to about 0.01, 0.02,
0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5,
0.6, 0.7, 0.8, 0.9, or 1-ml/min or more. In some embodiments, the
controlled flow position provides a flow rate from about 0.006,
0.007, 0.008, 0.009, 0.01, or 0.02-ml/min to about 0.03, 0.04,
0.05, 0.06, 0.07, 0.08, 0.09 or 0.1-ml/min. In some embodiments,
the controlled flow position provides a flow rate from about
0.5-ml/hr to 4-ml/hr. Accordingly, in preferred embodiments, the
valve is configured and arranged to preclude tubing installation
when the valve is in a controlled flow position. Preferably, the
tubing is installed when the valve is in a gravity flow position
(e.g., FIG. 10C), wherein the valve is positioned such that the
tubing can be installed in a substantially straight (e.g., linear,
un-pinched) configuration.
[0845] In preferred embodiments, the vascular access device (e.g.,
the catheter and/or fluid coupler) and the tubing 606 (e.g., tubing
assembly 606a) are configured and arranged to substantially
preclude twisting (e.g., rotational movement) between the vascular
access device and the tubing when engaged (e.g., fluidly connected,
in fluid communication with each other). Accordingly, in some
embodiments, the interconnecting portions of the vascular access
device and the tubing include a mechanical structure configured to
prevent rotational movement of the connection past a predetermined
point. For example, the interconnection of the vascular access
device and the tubing includes a Leur lock, wherein the vascular
access device includes the female portion of the Leur connection
and the tubing includes the male portion of the Leur connection. In
one embodiment, the female portion of the Leur connector includes a
groove configured to mate with a detent on the male portion of the
Leur connector, such that the male portion can be rotated within
the female portion only until the detent enters the groove. In one
embodiment, additional mechanisms for prevent twisting between the
vascular access device and the tubing are contemplated in the
preferred embodiments.
[0846] Free Flow Mitigation
[0847] As described herein, the valve includes a gravity flow valve
position, which allows fluid to flow freely through the valve and
into the host. In preferred embodiments, the system is configured
to regulate the amount of fluid allowed to flow into the host,
since unregulated flow (e.g., free flow) of IV solution into the
host could be deleterious to the host's health. For example, if the
IV solution contained a drug, such as insulin or heparin, infusion
of too much IV solution could cause an unsafe drop in blood sugar
or an unsafe decrease in the host's ability to form blood clots,
respectively. However, in certain circumstances, such as a power
failure, the system can be inadvertently stopped in the gravity
flow valve position. Accordingly, to prevent unregulated flow
(e.g., free flow) of fluid into the host, such as in the event of a
power failure and/or related circumstances, in preferred
embodiments, the system includes a free flow mitigation device
biased in an occluded position. In some embodiments, the system is
configured and arranged such that the free-flow mitigation device
precludes flow through the tubing responsive to power removal
and/or loss of power to the system and/or flow control device. In
some embodiments, the free flow mitigation device 606e is
incorporated into the tubing assembly 606a, such that flow through
the tubing is blocked until the valve activates (e.g., opens) the
free flow mitigation device. In one exemplary embodiment, the free
flow mitigation device 606e is a spring-clip occluder that closes
(e.g., blocks, pinches, occludes) the tubing until it is activated.
For example, in some embodiments, the valve includes an electronic
solenoid 807 that is configured and arranged to activate the
spring-clip occluder (e.g., causes the spring-clip occluder to
open, such that fluid can flow through the tubing, biases the free
flow mitigation device in an un-occluded position), when the tubing
is installed in the valve. In preferred embodiments, the free flow
mitigation device 606e is located within the tubing 606a such that
the free flow mitigation device is aligned with the portion of the
valve that activates it. For example with reference to FIG. 10A,
the valve includes an electronic solenoid 807 located along grove
803, such that (when the tubing assembly is installed) the
spring-clip occluder 606e is aligned with the electronic solenoid.
In preferred embodiments, the electronic solenoid is configured and
arranged such that free flow mitigation device returns to the
occluded position (e.g., blocks free flow) responsive to power
removal, such as during a power failure, during installation of the
tubing into the valve (e.g., at the beginning of a sensor session),
turning the system off (e.g., at the end of use and/or of a sensor
session), and the like. Preferably, the system is configured and
arranged for electronic control of the free flow mitigation device.
For example, in preferred embodiments, the valve controls the flow
of fluid into the host and drawback of samples for testing,
according to a flow profile (described elsewhere herein). In
preferred embodiments, the system is configured to electronically
control the opening and closing of the free flow mitigation device
(e.g., by energizing and de-energizing the solenoid) in response to
the flow profile. For example, when the flow profile specifies
infusion into the host or sample drawback, the system
electronically activates the solenoid, which in turn biases the
free flow mitigation device in the open position, so that the fluid
can be infused, samples can be drawn back to the analyte sensor,
samples can be returned to the host, the analyte sensor can be
washed with infusion solution, drugs can be infused, and the like.
Some free flow mitigation devices suitable for use with the present
system can be found in U.S. Pat. Nos. 5,810,323, 6,142,979, and
6,749,591, all of which are incorporated by reference herein in
their entirety.
[0848] Sample-Contacting Sensor
[0849] In preferred embodiments, the integrated sensor system 600
is configured such that at least the sensor's electroactive
surfaces can be exposed to a sample and the sample's analyte
concentration can be detected. Contacting the sensor 14 with the
sample can be accomplished in a variety of ways, depending upon
sensor and/or catheter configuration. A wide variety of catheter 12
and/or sensor 14 configurations can be implemented in the preferred
embodiments, to expose the sensor's electroactive surfaces to a
biological sample. In one exemplary embodiment, the catheter 12 is
disposed in the host's peripheral vascular system, such as in a
peripheral vein or artery, and a blood sample is taken up into the
catheter 12 such that the blood contacts the sensor's electroactive
surfaces. In another exemplary embodiment, the catheter 12 can be
disposed in the host's central vascular system or in an
extracorporeal blood flow device, such as but not limited to an
arterial-venous shunt, an extravascular blood-testing apparatus, a
dialysis machine and the like, wherein blood samples can be taken
up into the catheter 12 such that at least the sensor's
electroactive surfaces are contacted by the drawn up blood
sample.
[0850] In one exemplary embodiment, the sensor 14 is configured to
reside within the catheter lumen 12a (e.g., not protrude from the
catheter tip); and the integrated sensor system 600 is configured
to draw back a sample into the catheter lumen 12a such that at
least the sensor's electroactive surfaces are contacted by the
sample. In some embodiments, the sensor 14 is a small-structured
sensor having a width of less than about 1 mm. In one preferred
embodiment, the sensor has a width of less than about 0.4 mm. In a
more preferred embodiment, the sensor has a width of less than
about 0.2 mm. In some embodiments, the catheter 12 has an internal
diameter of from about 0.2 mm or less to about 2.0 mm or more,
preferably from about 0.5 mm to about 1.0 mm. In some embodiments,
the sensor 14 is configured such that its electroactive surfaces
are at or adjacent to its tip, and the flow control device 604 is
configured to take up sample into the catheter lumen 12a until the
sample covers at least the electroactive surfaces. In some
embodiments, the electroactive surfaces are distal from the
sensor's tip and sample is drawn farther back into the catheter
lumen 12a until the sample covers the electroactive surfaces. In
some embodiments, the tip of the sensor is disposed about 3 cm, 2
cm, or 1 cm or less from a tip of the catheter.
[0851] In some embodiments, the sample taken up into the catheter's
lumen 12a covers only a portion of the sensor's in vivo portion. In
other embodiments, the sample taken up into the catheter's lumen
12a covers the entire in vivo portion of the sensor 14. In some
embodiments, a sample volume of from about 1 .mu.l or less to about
2 ml or more is taken up into the catheter 12 and is sufficient to
cover at least the electroactive surfaces of the sensor 14. In some
preferred embodiments, the sample volume is from about 10 .mu.l to
about 1 ml. In some preferred embodiments, the sample volume is
from about 20 .mu.l to about 500 .mu.l. In other preferred
embodiments, the sample volume is from about 25 .mu.l to about 150
.mu.l. In more preferred embodiments, the sample volume is from
about 2 .mu.l to about 15 .mu.l.
[0852] In preferred embodiments, the sample taken up into the
catheter's lumen 12a remains within the in vivo portion of the
catheter 12. For example, in some embodiments, the sample is not
drawn so far back into the catheter 12 that it enters the ex vivo
portion of the catheter 12, the tubing 606 or the reservoir 602. In
some embodiments, however, the sample can be drawn back as far as
the catheter but not into the IV tubing. In some embodiments
wherein the catheter 12 is implanted in a host, the blood sample
never leaves the host's body (e.g., a plane defined by the host's
skin). In some embodiments wherein the catheter 12 is implanted in
an extracorporeal device, the sample does not substantially exit
the extracorporeal device. In preferred embodiments, wherein blood
is taken up into the catheter 12, the blood is returned to the host
(or extracorporeal device), which is described elsewhere herein. In
preferred embodiments, the sample is blood taken up from the host's
circulatory system and into the catheter 12 disposed within the
circulatory system.
[0853] In another exemplary embodiment of the integrated sensor
system, the sensor is configured to protrude from the catheter's
orifice 12b, at least intermittently. In preferred embodiments, the
sensor is configured to protrude sufficiently far out of the
catheter's lumen 12a (e.g., into the circulatory system proper)
that the sensor's electroactive surfaces are contacted by sample
(e.g., blood). In a further embodiment, the sensor is configured to
intermittently protrude from the catheter orifice 12b, such as by
moving back and forth, such that the electroactive surfaces are
alternately disposed within the catheter 12 and outside of the
catheter 12. In one exemplary embodiment of a catheter is implanted
in a host's vein, calibration solution 602a is provided within the
catheter 12 such that the sensor 14 is disposed within the catheter
12, the sensor 14 is contacted by the calibration solution 602a and
calibration measurements can be obtained periodically, when the
sensor 14 (e.g., electroactive surfaces) is moved outside of the
catheter 12, the sensor 14 is contacted by blood and blood analyte
measurements can be obtained.
[0854] In some embodiments of the integrated sensor system 600, the
catheter 12 and sensor 14 are configured to take advantage of flow
dynamics within the host's vascular system. By taking advantage of
flow dynamics, the system can be simplified, such that the flow
control device functions mainly to allow or block the flow of
calibration solution.
[0855] FIG. 9 is a cut-away illustration of one exemplary
embodiment, in which a catheter 12 is implanted in a host's vessel
906, such as but not limited to an artery or vein. The catheter 12
includes a sidewall 904 that can be configured to include one or
more holes 902 (e.g., orifices or openings configured for fluid
passage, such as from the exterior sidewall surface into the
catheter lumen 12a). The catheter 12 can be inserted into the
host's vein (or artery, or an extracorporeal circulatory device)
such that the catheter points either in the direction of blood flow
(antegrade) or against the direction of blood flow (retrograde).
The catheter is configured such that in an antegrade position,
blood flows into the catheter lumen 12a via the holes 902 and then
out of the catheter orifice 12b. In a retrograde position, blood
enters the catheter lumen 12a via the catheter orifice 12b and
flows out of the lumen through the holes 902. In some embodiments,
the sensor 14 can be disposed within the catheter lumen 12a such
that blood flowing between the holes 902 and the orifice 12b
contacts at least the sensor's electroactive surfaces. In some
embodiments, the sensor 14 is configured to be substantially
immobile within the lumen 12a, while in other embodiments the
sensor 14 is configured to be substantially moveable within the
lumen 12a, as described in more detail elsewhere herein.
[0856] Generally, the holes 902 can be placed in any location on
the catheter's sidewall 904. In some embodiments, the holes 902 can
be located near or adjacent to the catheter orifice 12a. In other
embodiments, the holes 902 can be placed remotely from the catheter
orifice 12a. The size, shape and number of holes 902 can be
selected to optimize the sample volume and flow rate through the
catheter lumen 12a. For example, in some embodiments, the holes 902
are round, ellipsoid, rectangular, triangular, star-shaped,
X-shaped, slits, combinations thereof, variations there of, and the
like. Similarly, in some embodiments, the catheter 12 can have from
1 to about 50 or more holes 902. In other embodiments, the catheter
can have from 2 to about 10 or more holes 902.
[0857] In some alternative embodiments, the catheter includes at
least one size wall orifice in place of an end tip orifice, which
allows selective exposure of the sensor to the host's biological
sample there through. A variety of alternative catheter
configurations are contemplated in conjunction with the preferred
embodiments.
[0858] In one exemplary embodiment of the integrated sensor system
600, the flow control device 604 is configured to intermittently
block the infusion of solution 602a through the catheter 12, which
is configured with side holes 902 as described above. Additionally,
the analyte sensor is disposed within the catheter lumen 12a such
that sample passing between the side holes 902 and the catheter
orifice 12b bathes the sensor's electroactive surfaces, during
which time an analyte measurement can be obtained. When the flow
control device 604 does not block infusion, the solution 602a
contacts the sensor's electroactive surfaces; and calibration
measurements can be taken.
[0859] In some embodiments, a solution 602a can be infused into the
catheter 12 at a rate such that the flow of sample between the
holes 902 and the orifice 12b is substantially blocked and at least
the electroactive surfaces are bathed in the solution 602a (e.g.,
undiluted solution). In preferred embodiments, the sensor 14 can be
calibrated while it is bathed in the undiluted solution 602a.
[0860] In preferred embodiments, the sensor 14 is a
small-structured sensor with at least one electrode, such as a
working electrode, as described elsewhere herein. In some
embodiments, the sensor 14 has two or more electrodes, such as but
not limited to working, reference and counter electrodes. In some
embodiments, the sensor 14 includes a reference electrode disposed
remotely from the working electrode, as discussed elsewhere herein.
In some embodiments, the sensor 14 includes two or more electrodes
that are separated by an insulator, such as described in U.S.
Patent Publication No. US-2007-0027385-A1, herein incorporated by
reference in its entirety. In preferred embodiments, the electrode
is a fine wire, such as but not limited to a wire formed from
platinum, iridium, platinum-iridium, palladium, gold, silver,
silver chloride, carbon, graphite, gold, conductive polymers,
alloys and the like. In some exemplary embodiments, the sensor 14
includes one or more electrodes formed from a fine wire with a
diameter of from about 0.001 or less to about 0.010 inches or more.
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.
[0861] In some embodiments, one or more electrodes are disposed on
a support, such as but not limited to a planar support of glass,
polyimide, polyester and the like. In some exemplary embodiments,
the electrodes include conductive inks and/or pastes including
gold, platinum, palladium, chromium, copper, aluminum, pyrolitic
carbon, composite material (e.g., metal-polymer blend), nickel,
zinc, titanium, or an alloy, such as cobalt-nickel-chromium, or
titanium-aluminum-vanadium, and are applied to the support using
known techniques, such as but not limited to screen-printing and
plating. Additional description can be found in U.S. Pat. No.
7,153,265, U.S. Patent Publication No. US-2006-0293576-A1, U.S.
Patent Publication No. US-2006-0253085-A1, U.S. Pat. Nos.
7,003,340, and 6,261,440, each of which is incorporated in its
entirety by reference herein.
[0862] In some embodiments, an optional redundant sensor can be
disposed within the catheter lumen, in addition to the sensor 14
described elsewhere herein. In one exemplary embodiment, a sensor
14 and a redundant sensor are disposed within the lumen of a sensor
implanted in a host's peripheral vein, such that the electroactive
surfaces of the sensor 14 are more proximal to the catheter orifice
12b than the electroactive surfaces of the redundant sensor;
wherein blood is taken up into the lumen 12a such that the
electroactive surfaces of both the sensor 14 and the redundant
sensor are contact by the blood; such that analyte can be detected
by both the sensor 14 and the redundant sensor and the redundant
sensor measurements are used by the system 600 to confirm the
sensor's 14 measurements. In a further embodiment, both the sensor
14 and the redundant sensor are intermittently concurrently
contacted by the solution 602a such that both the sensor 14 and the
redundant sensor can take calibration measurements of the solution
602a, wherein the calibration measurements of the redundant sensor
are at least used to confirm the calibration measurements of the
sensor 14. In another embodiment, the calibration measurements from
both the sensor 14 and the redundant sensor are used to calibrate
the sensor 14.
[0863] Local Analyzer
[0864] Referring to FIGS. 6 and 7, in some embodiments, the
integrated sensor system 600 includes a local analyzer 608
configured to operably connect to a remote analyzer 610. In some
embodiments, the local analyzer 608 is proximal to an analyte
sensor 14 and the remote analyzer 610 is configured to operably
connect to the local analyzer. However, alternative configurations
are possible, such as the analyte sensor 14 can be operably
connected to both the local and remote analyzers 608, 610
respectively. The remote analyzer 610 of the preferred embodiments
is discussed below. In various embodiments, one or more functions
of the local analyzer 608 can be transferred to the remote
analyzer, as is appreciated by one skilled in the art. Likewise, in
some embodiments, one or more functions of the remote analyzer 610
can be incorporated into the local analyzer 608. In further
embodiments, functions of the local and/or remote analyzers 608,
610 can be disposed in one, two, three or more physical bodies
(e.g., separate housings), depending upon the integrated sensor
system 600 configuration and/or component combinations. For
example, in one embodiment, the local analyzer 608 includes a
potentiostat, a power source (e.g., battery or connection to an
electrical source), and data storage; and the local analyzer 608 is
configured such that the potentiostat is disposed on the sensor's
fluid coupler 20 and the remaining local analyzer 608 components
are disposed elsewhere between the local analyzer 608 and the
remote analyzer 610 (e.g., connected by wiring).
[0865] Operable connections between the local and remote analyzers
608, 610 and the analyte sensor 14 can be accomplished by a hard
wire (e.g., USB, serial), RF communication, IR communication, and
the like. In some embodiments, operable connections include a
connector known in the art, such as but not limited to mating plug
and socket units, screw connectors, clips and the like. In some
embodiments, the connectors are separable. In other embodiments,
the connectors are inseparable. In some embodiments, the connectors
include a lock, to prevent inadvertent disconnection. In some
embodiments, the local analyzer can be isolated from the remote
analyzer by an isolation transformer.
[0866] In some embodiments, the local analyzer 608 is operably
connected to the sensor 14 (e.g., the sensor electrode(s)), such as
by a wire connection. A detailed description of electronic
components and configurations is described elsewhere herein, for
example, in the section entitled "Sensor Electronics." In some
embodiments, the local analyzer 608 is disposed on or adjacent to
the sensor, such as on the sensor fluid coupler 20. In one
exemplary embodiment, the sensor's fluid coupler 20 includes a
local analyzer housing that includes at least a potentiostat. In
some embodiments, the housing can include a battery and
electronics, such that the sensor 14 can be powered, and data can
be collected and/or transmitted to additional system electronics
(e.g., electronics units disposed remotely from the sensor, such as
on the host's arm, on the host's bed and in the remote analyzer,
and the like). In some embodiments, the local analyzer 608 includes
a small housing that is connected to the sensor 14 via a short wire
(e.g., from about 1 cm or less to about 10 cm or more) and is taped
to the host's skin, such as adjacent to the catheter's insertion
site on the host's arm or hand. In a further embodiment, the local
analyzer 608 includes a connector, such as but not limited to a
"plug" configured to mate with a "socket" wired to the sensor 14,
such that an electrical connection can be made between the local
analyzer 608 and the sensor 14. In another embodiment, the sensor
14 includes a cable having a plug configured to connection to the
local analyzer 608 via a socket. In still another embodiment, both
the sensor 14 and the local analyzer 608 include cables configured
to mate with each other via a plug and socket mechanism.
Advantageously, a detachable configuration allows catheter/sensor
insertion without a cumbersome connection to the local analyzer 608
as well as re-use of the local analyzer 608. In an alternative
exemplary embodiment, the local analyzer 608 is permanently
connected to the sensor 14 and cannot be disconnected therefrom; a
single use, permanently connected configuration can simplify
application to the host, can reduce the possibility of
cross-contamination between hosts, does not require cleaning and/or
sterilization between hosts, and can reduce operator error during
application to the host.
[0867] In preferred embodiments, the local analyzer 608 includes at
least the minimal electronic components and/or programming required
to energize the sensor 14 and collect data therefrom, such as but
not limited to a potentiostat. However, in some embodiments, the
local analyzer 608 includes additional electronic components that
can be programmed to analyze one or more components of the
collected raw signal, or to store data, calibration information, a
patient ID and the like. In one exemplary embodiment, the local
analyzer 608 includes a potentiostat and a battery back up. The
battery back up can maintain a potential on the sensor and store
data (calibration and/or collected host data) for brief periods of
time when the electronics can be disconnected, such as when the
host is moved from one location to another. In one exemplary
embodiment, the local analyzer 608 is disposed on or adjacent to
the sensor 14 and is configured such that the host can be connected
to a first remote analyzer 610 at one station, and then
disconnected from the first remote analyzer 610, moved to a new
location and connected to a second remote analyzer 610 at the new
location, and the local analyzer 608 retains sufficient data that
the system 600 functions substantially without initialization or
substantial delay upon connection to the new (second) remote
analyzer 610. In another example, the host can be disconnected from
the first remote analyzer 610, taken to another location for a
procedure (e.g., for surgery, imaging, and the like) and then
reconnected to the first remote analyzer 610 upon return to the
original location without substantial loss of system 600 function
upon reconnection.
[0868] In some embodiments, the local analyzer 608 includes two or
more parts, such that only the potentiostat is disposed on or
adjacent to the sensor 14 (e.g., sensor fluid coupler 20) or the
catheter (e.g., catheter connector 18); other portions of the local
analyzer 608 can be disposed remotely from the host, such as in a
separate housing wired to the sensor and to the remote analyzer. In
one exemplary embodiment, the two parts of the local analyzer 608
can be separated (e.g., unplugged) such that the host can be moved
and the local analyzer 608 portion that is attached to the host
goes with the host while the remaining portion stays with the
remote analyzer 610.
[0869] In still other embodiments, all sensor electronics
components are disposed remotely from the host, such as in the
remote analyzer 610. For example, the sensor 14 can include an
appropriate connector, plug and/or wiring to connect the sensor 14
to the remote analyzer 610, which powers the sensor 14, collects
raw data from the sensor 14, calibrates the sensor 14, analyzes and
presents the data, and the like. In one example, the sensor 14
includes a cable of sufficient length to permit plugging the sensor
14 into a remote analyzer 610 disposed at the host's bedside.
[0870] In still other embodiments, the local analyzer 608 can be
incorporated into the remote analyzer 610, such as housed in the
same body as the remote analyzer 610, for example. In one exemplary
embodiment, both the local and remote analyzers 608, 610 are
disposed in a housing attached to a support 612 (e.g., connected to
an IV pole, placed on a bedside table, connected to the wall,
clamped to the head of the host's bed) and connected to the analyte
sensor via a wire or cable. In some embodiments, the cables/wires
(e.g., for connecting the sensor to the local analyzer and/or the
remote analyzer, and/or connecting the local analyzer to the remote
analyzer) can be provided in the IV tubing set.
[0871] Remote Analyzer
[0872] As discussed in the section entitled "Local Analyzer," the
integrated sensor system 600 includes a remote analyzer 610. In
preferred embodiment, the remote analyzer 610 is configured to at
least communicate with the local analyzer 608 and can be configured
to control the flow control device 604 described in the sections
entitled "Flow Control Device," and "Flow Control Device Function."
Generally, the remote analyzer 610 is powered from a standard 120
VAC wall circuit or other suitable power source, for example. In
some embodiments, the remote analyzer 610 is disposed at the host's
bedside and can be configured to be disposed on a support 612, such
as but not limited to, mounted a mobile IV drip pole, attached to
the wall, clamped to the host's bed, or sitting on a table or other
nearby structure.
[0873] In preferred embodiments, the remote analyzer 610 includes a
display, such as but not limited to a printout, an LED display, a
monitor, a touch-screen monitor and the like. In some embodiments,
the remote analyzer 610 includes both a hard copy display, such as
a printer configured to print collected data, and a monitor. In
some embodiments, the remote analyzer 610 is a programmable
touch-screen panel PC configured to have different "screens" and
"buttons" for control of system components (e.g., the sensor 14,
the flow control device 604, etc.) and to display data, such as but
not limited to host identification and condition, host food intake,
medication schedules and dosage information, sensor identification,
raw data, processed data, calibration information, and the like,
such as in tables and/or graphs. In further preferred embodiments,
the remote analyzer 610 is configured to be programmed, such that
the operator can initiate system functions such as IV fluid line
priming, starting and/or stopping the flow control device 604,
select among two or more solutions (e.g., between glucose
concentrations), select the mode of data delivery (e.g., printer or
on-screen), send data to a central location (e.g., the nurse's
station or medical records), set alarms (e.g., for low and high
glucose), and the like.
[0874] In some embodiments, the system 600 is configured to
integrate with (e.g., be used in conjunction with) third party
medical devices, such as but not limited to a pulse-oxygen meter, a
blood pressure meter, a blood chemistry machine, and the like. In
such embodiments, the local and/or remote analyzers 608, 610 can be
configured to communicate with the third party medical devices,
such as but not limited to a patient monitor.
[0875] Flow Control Device Function
[0876] In some embodiments, the remote analyzer 610 controls the
function of the flow control device 604. In some embodiments, the
flow control device includes electronics configured to control the
flow control device. The flow control device 604 can be configured
to perform a number of steps of operation, which are discussed
below. Depending upon the system configuration and physician
preferences, in some embodiments, one or more of the steps can be
performed. In some embodiments, all of the steps are performed. In
some embodiments, the steps of operation can be performed in the
order in which they are presented herein. In other embodiments, the
order of steps of operation can be varied (e.g., repeated, omitted,
rearranged), depending upon various parameters, such as but not
limited to the calibration solution 602a selected, the particular
infusion set selected, catheter 12 size, host condition, analyte of
interest, type of sample and location of sample collection,
integration with third party devices, additional infusion of fluids
and the like.
[0877] FIGS. 8A through 8C are schematic illustrations of a flow
control device in one exemplary embodiment, including its relative
movement/positions and the consequential effect on the flow of
fluids through the sensor/catheter inserted in a host. In general,
steps performed by the flow control device 604, include the steps
of: contacting the sensor 14 with calibration solution 602a
(including sensor calibration) and contacting the sensor with a
biological sample to be measured. In some embodiments, additional
steps can be taken, such as but not limited to keep a vein open
(KVO) step and a wash step. In the exemplary embodiment presented
in FIGS. 8A though 8C, the flow control device 604 is a roller
valve configured to move between at least two positions, 810 and
812, respectively. Movement of the flow control device 604 between
positions 810 and 812 effectively concurrently moves the pinch
point 808 (e.g., the point at which tubing 606 is pinched) between
positions 810 and 812. Additional flow control device positions are
discussed below.
[0878] The top of FIGS. 8A through 8C are schematic drawings
illustrating positions of the flow control device 604. The bottom
of FIGS. 8A through 8C, are a cut-away views of an implanted
catheter 12, including an indwelling sensor 14, illustrating the
corresponding activity at the implantation site, in response to
movements of the flow control device 604. For simplicity, for
purposes of discussion only, it is assumed that the catheter 12 is
implanted in a host's vein, that the sensor 12 does not protrude
from the catheter's orifice 12b and that the catheter 14 does not
include side holes 902. However, one skilled in the art appreciates
that the catheter 14 could be implanted into any vessel of the host
or into a variety of extracorporeal devices discussed elsewhere
herein.
[0879] Step One: Contacting Sensor with Calibration Solution
[0880] In general, the system is configured to allow a calibration
solution to contact the sensor using a flow control device such as
a pump, valve or the like. In some embodiments, such as shown in
FIGS. 8A through 8C, the flow control device 604 is a valve
configured with a first structure 802 and a second structure 806.
For convenience, the first structure 802 is depicted as a roller
connected to a rotatable axle 804, however any flow control device
such as described in the section entitled "Flow Control Device,"
can be configured to utilize the concepts and/or functions
described herein. In general, when the flow control device is a
valve, the valve is configured to allow no flow, gravity flow
and/or metered flow through movement of the valve between one or
more discreet positions.
[0881] In the embodiment shown in FIGS. 8A through 8C, the flow
control device 604 is configured such that a tube 606 threaded
between the first and second structures 802, 806 (e.g., between the
roller and the surface against which the roller presses) is
compressed substantially closed. For convenience, the compressed
location on the tubing is referred to herein as the "pinch point"
808. In some embodiments, the flow control device 604 is configured
such that the pinch point is moved along the tubing, either closer
to or farther from the host. As the pinch point 808 is moved closer
to the host, the tube 606 is progressively compressed, causing
fluid (e.g., solution 602) to be pushed into the host's vascular
system (see the corresponding illustration of the sensor within the
host's vessel at the bottom of FIG. 8A), at the catheter 12
implantation site. Conversely, as the pinch point 808 is moved away
from the host, the portion of tubing 606 on the host side of the
pinch point 808 progressively expands, causing sample (e.g., blood)
to be drawn up into the catheter lumen 12a. In an alternative
embodiment, the flow control device 604 is configured such that the
pinch point is substantially stationary and the first and second
structures selectively compress the tubing at the pinch point
(e.g., the tube 606 is either pinched fully closed or is fully
open), which either stops or allows the flow of solution 602a.
[0882] In the exemplary embodiment shown in FIG. 8A (bottom), the
catheter 12 is implanted in the host's vein 906 (or artery), as
described elsewhere herein. A sensor 14 is disposed with the
catheter 12. The catheter 12 is fluidly connected to a first end of
tubing 606 that delivers the solution 602a to the catheter 12. The
solution 602a can move out of the catheter 12 and a sample of blood
814 can move in and out of the catheter 12, via the catheter's
orifice 12b. In some alternative embodiments, the catheter 12
includes optional sidewall holes 902 (see FIG. 9, described
elsewhere herein) and the solution 602a and blood can move in and
out of the catheter 12 via the sidewall holes 902 and the catheter
orifice 12b. In some alternative embodiments, the sensor is
configured to move in and out of the catheter. In some embodiments,
the catheter orifice 12b is disposed in the sidewall 904 (e.g.,
near the catheter's tip) instead of at the tip. Tubing 606 is
fluidly connected to the reservoir 602 on a second end (see FIGS. 6
and 7).
[0883] Referring now to a calibration phase to be performed by the
exemplary valve of FIG. 8A, in preferred embodiments, the flow
control device 604 is configured to perform a step of contacting
the sensor 14 with solution 602a, wherein the flow control device
604 moves from position 810 to position 812 (e.g., forward, toward
the host/catheter). When the flow control device 604 moves from
position 810 to position 812, the pinch point 808 is moved from
position 810 to position 812. As the pinch point 808 is moved from
position 810 to position 812, a first volume of the calibration
solution 602a is pushed through the tubing 606, toward the catheter
12.
[0884] Referring again to the bottom of FIG. 8A, a second volume of
the solution 602a, which is substantially equal to the first
volume, is pushed into the host's vein 906, in response to the
first volume of solution 602a moving toward the host. As the second
volume of solution 602a is pushed through the catheter 12 and into
the host's vein the second volume contacts (e.g., bathes) the
analyte sensor 14, including the analyte sensor's electroactive
surfaces. In some embodiments, the volume (e.g., the first and
second volumes of fluid) moved is from about 3 .mu.l or less to
about 1 ml or more. In some preferred embodiments, the volume is
from about 10 .mu.l to about 500 .mu.l, or more preferably from
about 15 .mu.l to about 50 .mu.l. In general, the volume of fluid
pushed through the catheter in a particular phase (e.g.,
calibration phase) is dependent upon the timing of the phase. For
example, if a long phase, such as a 20 minute calibration phase
(e.g., as compared to a shorter 5 minute phase) were selected, the
volume of fluid pushed during the long phase would be 4.times.
greater than the volume of fluid pushed during the shorter phase.
Accordingly, one skilled in the art appreciates that the above
described ranges of fluids infusion can be increased and/or
decreased simply be increasing or decreasing the measurement phase
and/or intervals (i.e., timing). In preferred embodiments, the
fluid is moved at a flow rate that is sufficiently slow that the
calibration solution's temperature substantially equilibrates with
the temperature of the tissue surrounding the in vivo portion of
the catheter and/or temperature of bodily fluid (e.g., blood), such
that the temperature of the calibration solution and the
temperature of the blood are substantially the same. In preferred
embodiments, the flow rate is from about 0.95, 0.9, 0.85, 0.8,
0.75, 0.7, 0.65, 0.6, 0.55, 0.5, 0.45, 0.4, 0.35, 0.3, 0.25, 0.2,
0.15, 0.1, 0.05, 0.01, 0.001 .mu.l/min or less to about 1, 1.5, 2,
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10.0
ml/min or more. In one exemplary embodiment, the flow control
device 604 maintains a flow rate from about 0.9, 0.8, 0.7, 0.6,
0.5, 0.4, 0.3, 0.2, 0.1 or 0.05 ml/min or less to about 1.0, 1.1,
1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more. In
one exemplary embodiment, the flow rate is from about 1 .mu.l/min
to about 1.0 ml/min. In one exemplary embodiment, the flow rate is
from about 0.01 ml/min to about 0.2 ml/min. In another exemplary
embodiment, the flow rate is from about 0.05 ml/min to about 0.1
ml/min. In some embodiments, the flow rate is 0.0 ml/min.
[0885] In some embodiments, the system is configured such that the
speed of the movement between the first and second discreet
positions is regulated or metered to control the flow rate of the
fluid through the catheter. In some embodiments, the system is
configured such that the time of movement between the first and
second discreet positions is from about 0.001, 0.005, 0.01, 0.02,
0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25,
0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or 1.0 seconds or less to about
1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9,
9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,
25, 26, 27, 28, 29 or 30 seconds or more, preferably from about 0.5
to 10 seconds. In some embodiments, the system is configured such
that an amount of pinch of the tubing regulates the flow rate of
the fluid through the catheter. In some embodiments, the fluid flow
is regulated through a combination of metering and/or pinching
techniques, for example. Depending on the type of flow control
device (e.g., valve), a variety of methods of metering and/or
regulating the flow rate can be implemented as is appreciated by
one skilled in the art.
[0886] Preferably, the sensor is configured to measure a signal
associated with the solution (e.g., analyte concentration) during
the movement of the flow control device from position 810 to
position 812 and/or during contact of the sensor 14 with the
solution 602a. Electronics, such as an electronic module included
in either the local or remote analyzer 608, 610 controls signal
measurement and processing, such as described in more detail
elsewhere herein.
[0887] In general, a calibration measurement can be taken at any
time during the flow control device 604 movement from position 810
to position 812, and including a stationary (stagnant) time there
after. In some embodiments, one or more calibration measurements
are taken at the beginning of the flow control device 604 movement
from position 810 to position 812. In other embodiments, one or
more calibration measurements are taken at some time in the middle
of the flow control device 604 movement from position 810 to
position 812. In some embodiments, one or more calibration
measurements are taken near the completion of the flow control
device 604 movement from position 810 to position 812. In some
embodiments, one or more calibration measurements are taken after
completion of the flow control device 604 movement from position
810 to position 812. In still other embodiments, the flow control
device is positioned such that fluid can flow followed by
positioning the flow control device such that there is no fluid
flow (e.g., 0 ml/min) during the calibration measurement. In
preferred embodiments, one or more calibration measurements are
taken when the temperature of the solution 602a has substantially
equilibrated with the temperature of the tissue surrounding the in
vivo portion of the implanted catheter 12. Processing of
calibration measurements and sensor calibration are described
elsewhere herein.
[0888] As a non-limiting example, in some embodiments, the sensor
can be calibrated using one or more reference solutions. For
example, if the analyte is glucose, a suitable reference (e.g.,
calibration solution) is saline containing 0, 25, 50, 75, 100, 125,
150, 175, 200, 225, 250, 275, 300 mg/dl glucose or more. In some
embodiments, two or more such reference solutions can be used to
calibrate the sensor. In some embodiments, a baseline value of the
sensor can be obtained by generating a signal when the sensor is
exposed to a 0 mg/dl reference solution (e.g., 0 mg/dl analyte). In
some embodiments, updated baseline values are continuously obtained
by repeatedly exposing the sensor to the 0 mg/dl reference
solution, such as every 1, 2, 3, 4, 5, 10, 20, 30, 40, 50, or 60 or
more minutes. In some embodiments, updated baseline values are
continuously obtained by exposing the sensor to the 0 mg/dl
reference solution for periods of time and continuously collecting
baseline values. For example, the sensor can be exposed to the 0
mg/dl reference solution for 5, 10, 15, 20, 25, 30, 40, 50, or 60
minutes, or longer, while baseline signals are continuously
generated. In this embodiment, sensitivity m calibration values can
be obtained intermittently by exposing the sensor to an
analyte-containing reference solution intermittently, such as but
not limited to every 5, 10, 15, 20, 25, 30, 40, 50, or 60 minutes,
or longer, such as at the conclusion of the exposure to the 0 mg/dl
solution. In other embodiments, such calibrations measurements
(e.g., to obtain a baseline value) are performed "intermittently,"
such as once every 24 hours.
[0889] In some embodiments, sensitivity m calibration values are
obtained substantially continuously/continually, such as by
exposure of the sensor to one or more analyte-containing reference
solutions every 1, 2, 3, 4, 5, 10, 20, 30, 40, 60 or more minutes.
In some embodiments, sensitivity m calibration values are obtained
substantially continuously/continually by exposure of the sensor to
one or more analyte-containing reference solutions for a period of
time, such as but not limited to for 5, 10, 15, 20, 25, 30, 40, 50,
or 60 minutes, or longer, while sensitivity signals are
continuously generated. In one exemplary embodiment, continuous
calibration measurements are performed by passing a 100-mg/dl
glucose calibration solution across the sensor (e.g., to detect
shifts in sensitivity m), and the intermittent calibration
measurements are performed to determine baseline b, by passing a
0-mg/dl calibration solution across the sensor. While not wishing
to be bound by theory, it is believed that in some circumstances,
baseline drift is greater than sensitivity drift. Accordingly, in
some embodiments, the system is configured to perform baseline
calibration measurements (with 0-mg/dl glucose) automatically
(e.g., every 5-minutes) and a sensitivity calibration measurement
(with 100-mg/dl) intermittently (e.g., every hour).
[0890] Step Two: Sample Collection and Measurement
[0891] In general, the system is configured to allow a sample
(e.g., blood) to contact the sensor using the flow control device.
Referring now to the top of FIG. 8B, the flow control device 604 is
configured to draw back (or take-in) a sample (e.g., blood) from
the host. For example, to collect a sample, the flow control device
604 reverses and moves backward (e.g., away from the
host/catheter), from position 812 to position 810, thereby causing
the pinch point 808 to move away from the host. As the pinch point
is moved from position 812 to position 810, the tube 606 (on the
host side of the pinch point 808) expands (e.g., the tube volume
increases).
[0892] Referring now to the bottom of FIG. 8B, as the tube volume
increases, a small, temporary vacuum is created, causing sample 814
(e.g., blood) to be taken up into the catheter lumen 12a. In some
embodiments, the flow control device 604 is configured to take up a
sufficient volume of sample 814 such that at least the sensor's
electroactive surfaces are contacted by the sample 814. In some
embodiments, a sample volume of from about 95, 90, 85, 80, 75, 70,
65, 60, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9.0, 8.0, 7.0, 6.0,
5.0, 4.0, 3.0, 2.0, 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or
0.1 .mu.l or less to about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,
0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0,
1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 ml or more is
taken up into the catheter 12 and is sufficient to cover at least
the electroactive surfaces of the sensor 14. In some embodiments,
the sample volume is from about 10 .mu.l to about 1 ml. In some
embodiments, the sample volume is from about 20 .mu.l to about 500
.mu.l. In other embodiments, the sample volume is from about 25
.mu.l to about 150 .mu.l. In other embodiments, the sample volume
is from about 2 .mu.l to about 15 .mu.l.
[0893] In some embodiments, the sample taken up into the catheter
is taken up substantially no farther than the skin (or a plane
defined by the skin of the patient). In some embodiments, the
sample is taken up into the catheter substantially no farther than
the catheter's inner lumen (e.g., substantially not into the IV
tubing.)
[0894] In some embodiments, the rate of sample take-up is
sufficiently slow that the temperature of the sample substantially
equilibrates with the temperature of the surrounding tissue.
Additionally, in some embodiments, the rate of sample take-up is
sufficiently slow such that substantially no mixing of the sample
814 and solution 602a occurs. In some embodiments, the flow rate is
from about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08,
0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007,
0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/min or less to about
1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or
more. In one exemplary embodiment, the flow rate is from about
0.001 ml/min or less to about 2.0 ml/min or more. In preferred
embodiments, the flow rate is from about 0.01 ml/min to about 1.0
ml/min. In one exemplary preferred embodiment, the flow rate is
from about 0.02 ml/min to about 0.35 ml/min. In another exemplary
preferred embodiment, the flow rate is from about 0.0.02 ml/min to
about 0.2 ml/min. In yet another exemplary preferred embodiment,
the flow rate is from about 0.085 ml/min to about 0.2 ml/min.
[0895] As described above, in some embodiments, the system is
configured such that the speed of the movement between the first
and second discreet positions is regulated or metered to control
the flow rate of the fluid through the catheter. In some
embodiments, the system is configured such that the time of
movement between the first and second discreet positions is from
about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08,
0.09, 0.1, 0.15, 0.2, 0.25, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 or
1.0 seconds to about 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5,
7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 seconds, preferably from
about 0.5 to 10 seconds. In some embodiments, the system is
configured such that an amount of pinch of the tubing regulates the
flow rate of the fluid through the catheter. In some embodiments,
regulate the fluid flow through a combination of metering and/or
pinching techniques, for example. Depending on the type of flow
control device (e.g., valve), a variety of methods of metering
and/or regulating the flow rate can be implemented as is
appreciated by one skilled in the art.
[0896] Measurements of sample analyte concentration can be taken
while the electroactive surfaces are in contact with the sample
814. An electronics module included in the local and/or remote
analyzer 608, 610 controls sample analyte measurement, as described
elsewhere herein. In some embodiments, one sample measurement is
taken. In some embodiments, a plurality of sample measurements are
taken, such as from about 2, 3, 4, 5, 6, 7, 8, 9, or 10
measurements to about 20, 25, 30, 35, 40, 45 or 50 or more
measurements and/or at a sample rate of from about 1 measurement
per second to about 1 measurement per minute. In some embodiments,
the rate is from about 1 measurement per 2 seconds to about 1
measurement per 30 seconds. In preferred embodiments, sample
measurements are taken substantially continuously, such as but not
limited to substantially intermittently, as described elsewhere
herein.
[0897] Optional Step: Flush
[0898] In some exemplary embodiments, the flow control device 604
is configured to perform one or more steps, in addition to steps
one and two, described above. A flush step, during which the sensor
14 and/or catheter 12 are substantially washed and/or cleaned of
host sample, is one such optional step.
[0899] Referring now to the top of FIG. 8C, the exemplary flow
control device 604 performs a flush step by moving forward from
position 810 (e.g., toward the host/catheter), past position 812
(e.g., around and over the top of structure 804) and back to
position 810. For convenience, the movement illustrated by an arrow
in the top of FIG. 8C is referred to herein as the "flush
movement."
[0900] Referring now to the bottom of FIG. 8C, the flush movement
pushes forward a volume of solution 602a (e.g., a third volume)
that pushes the collected blood sample 814 into the host. In some
embodiments, the third volume of solution 602a is substantially
equal to the first and second volumes described above. In some
embodiments, the flush movement is repeated at least one time. In
some embodiments, the flush movement is repeated two, three or more
times. With the exception of the first flush movement, which pushes
the sample 814 back into the host, each repeat of the flush
movement pushes a volume of solution 602a into the host, for
example. In some embodiments, the flush movement pushes the third
volume of solution 602a into the host at a rate of from about 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,
0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005,
0.004, 0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2,
1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5,
5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 ml/min or
more. In some embodiments the flush movement pushes the third
volume of solution into the host at a rate of from about 1.0
.mu.l/min to about 1.0 ml/min. In alternative embodiments, the flow
control device 604 is moved to a fully opened position (e.g., no
pinch) and the flow regulator 602b is set at a setting that allows
more solution (e.g., an increased volume and/or at a faster rate)
to infuse into the host than during the calibration phase (e.g.,
step one, above). In preferred embodiments, the flush movement
washes enough blood off of the analyte sensor's electroactive
surfaces that the sensor 14 can measure the solution 602a
substantially without any interference by any remaining blood. In
some embodiments, the flush step is incorporated into step one,
above.
[0901] Generally, the solution 602a is flushed through the catheter
12, to ensure that a sufficient amount of the sample has been
removed from the sensor 14 and the catheter lumen 12a, such that a
calibration measurement can be taken. However, in some embodiments,
sample is collected, measured and flushed out, followed by
collection of the next sample, substantially without sensor
calibration; the flush step can be executed between samples to
ensure that the sample being analyzed is substantially
uncontaminated by the previous sample. In some embodiments, a
relatively extended flush is used, while in other embodiments the
flush is just long enough to ensure no blood remains.
[0902] In some embodiments, the effectiveness of the flushing
movement is dependent upon the solution 602a composition (e.g.,
concentrations of sodium chloride, glucose/dextrose, anticoagulant,
etc.). Accordingly, the amount of solution 602a required to ensure
that substantially no sample remains in the catheter 12 and/or on
the sensor 14 can depend on the solution 602a composition. For
example, relatively more flush movements may be required to
completely remove all of the sample when a non-heparinized solution
is selected than when a heparinized solution is selected. In some
embodiments, the effectiveness of the flushing movement is also
dependent upon the flush flow rate. For example, a relatively
faster flow rate can be more effective in removing sample from the
sensor than a slower flow rate, while a slower flow rate can more
effectively move a larger volume of fluid. Accordingly, in some
embodiments, the number of flush movements selected is dependent
upon the calibration solution and flow rate selected. In some
embodiments, the flush step flow rate is from about 0.9, 0.8, 0.7,
0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04,
0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005, 0.004, 0.003,
0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2, 1.3, 1.4,
1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,
6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10.0 ml/min or more, and
last for from about 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, 9, 8,
7, 6, 5, 4, 3, 2, or 1 seconds or less to about 1, 1.1, 1.2, 1.3,
1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,
2.8, 2.9, or 3 minutes or more. In one exemplary embodiment, about
0.33 ml of solution 602a is flushed at a rate of about 1.0 ml/min,
which takes about 20 seconds.
[0903] In some embodiments, the flush step returns the sample 814
(e.g., blood) to the host, such that the host experiences
substantially no net sample loss. Further more, the flush movement
washes the sensor 14 and catheter lumen 12a of a sufficient amount
of sample, such that an accurate calibration measurement (e.g., of
undiluted solution 602a) can be taken during the next step of
integrated sensor system 600 operations. In some embodiments, the
number of sequential flush movements is sufficient to only wash
substantially the sample from the sensor 14 and catheter lumen 12a.
In other embodiments, the number of sequential flush movements can
be extended past the number of flush movements required to remove
the sample from the sensor and catheter lumen, such as to provide
additional fluid to the host, for example.
[0904] At the completion of the flush step, the flow control device
604 returns to step one, illustrated in FIG. 8A. In some
embodiments, the steps illustrated in FIGS. 8A through 8C are
repeated, until the system 600 is disconnected from the
catheter/sensor, either temporarily (e.g., to move a host to an
alternate location for a procedure) or permanently (e.g., at
patient discharge or expiration of sensor life time). In some
embodiments, additional optional steps can be performed.
[0905] Optional Step: Keep Vein Open (KVO)
[0906] Thrombosis and catheter occlusion are known problems
encountered during use of an IV system, such as when the fluid flow
is stopped for a period of time or flows at a too slow rate. For
example, thrombi in, on and/or around the catheter 12, such as at
the catheter's orifice 12b can cause an occlusion. Occlusion of the
catheter can require insertion of a new catheter in another
location. It is known that a slow flow of IV solution (e.g., saline
or calibration fluid; with or without heparin) can prevent catheter
occlusion due to thrombosis. This procedure is know as keep vein
open (KVO).
[0907] In general, to infuse a fluid into a host, the infusion
device must overcome the host's venous and/or arterial pressure.
For example, during infusion of a hydration fluid, the IV bag is
raised to a height such that the head pressure (from the IV bag)
overcomes the venous pressure and the fluid flows into the host. If
the head pressure is too low, some blood can flow out of the body
and in to the tubing and/or bag. This sometimes occurs when the
host stands up or raises his or her arm, which increases the venous
pressure relative to the head pressure. This problem can be
encountered with any fluid infusion device and can be overcome with
a KVO procedure. KVO can maintain sufficient pressure to overcome
the host's venous pressure and prevent "back flow" of blood into
the tubing and/or reservoir.
[0908] In some embodiments, the flow control device 604 can be
configured to perform a KVO step, wherein the fluid flow rate is
reduced (but not completely stopped) relative to the calibration
and/or wash flow rates. In preferred embodiments, the KVO flow rate
is sufficient to prevent the catheter 12 from clotting off and is
relatively lower than the flow rate used in step one (above). In
preferred embodiments, the KVO flow rate is sufficient to overcome
the host vessel pressure (e.g., venous pressure, arterial pressure)
and is relatively lower than the flow rate used in step one
(above). In some embodiments, the KVO flow rate is from about 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08, 0.07, 0.06,
0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007, 0.006, 0.005,
0.004, 0.003, 0.002 or 0.001 ml/min or less to about 1.0, 1.1, 1.2,
1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or more. In some
preferred embodiments, the KVO flow rate is from about 0.02 to
about 0.2 ml/min. In some more preferred embodiments, the KVO flow
rate is from about 0.05 ml/min to about 0.1 ml/min). In some
embodiments, the KVO flow rate is less than about 60%, 50%, 40%,
30%, 20%, or 10% of the calibration and/or flush flow rate(s). In
some embodiments, the KVO step is performed for from about 0.25
minutes or less to about 20 minutes or more. In preferred
embodiments, the solution 602a flows at a rate such that the
temperature of the solution 602a substantially equilibrates with
the temperature of the tissue surrounding the in vivo portion of
the catheter 12. Advantageously, equilibrating the solution 602a
temperature with that of the surrounding tissue reduces the effect
of temperature on sensor 14 calibration and/or sample measurement,
thereby improving sensor accuracy and consistency. In some
embodiments, the KVO step can be incorporated into one or more of
the flow control device steps of operation described elsewhere
herein, including steps one and two, and the flush step, above.
[0909] The KVO step can be executed in one or more ways. In some
embodiments, the flow control device 604 can be configured to move
to at least one addition position, wherein the tube 606 is
partially pinched. For example, the flow control device 604 is
configured to move to a position such that the pinch point 808 is
partially closed/open. For example, in the embodiment shown in
FIGS. 8A through 8C, the flow control device 604 can be moved
forward somewhat past position 812, such that the roller 802 causes
the tube 606 to be partially pinched. In another example, the flow
control device 604 can be moved backwards somewhat behind position
810, such that the roller 802 again causes the tube 606 to be
partially pinched. In preferred embodiment, the amount of pinch can
be adjusted such that the desired KVO flow rate can be achieved. In
some alternative embodiments, KVO is performed by moving the flow
control device between positions 810 and 812 (e.g., see FIG. 8A) at
a reduced speed, such that the flow rate is from about 0.1
.mu.l/min or less to about 0.5 ml/min or more. In some embodiments,
the system is configured such that the time of movement between the
first and second discreet positions is from about 0.25 to 30
seconds, preferably from about 5 to 15 seconds. In some preferred
embodiments, the tubing is pinched fully closed (e.g., between
structures 802 and 806) during the movement from position 810 and
812 (e.g., see FIG. 8A). In some preferred embodiments, after the
flow control device reaches position 812, the flow control device
flips over the top and back to position 810 (e.g., see FIG. 8C) at
a substantially rapid speed that the flow rate remains
substantially unchanged. In an even further embodiment, during the
KVO step the flow control device alternates between the slow and
fast movements at least two times, such that the KVO step lasts a
period of time.
[0910] In some circumstances, signal artifacts can occur due to the
location a catheter is implanted and if the host has moved his or
her arm (where the catheter is implanted/inserted) to certain
positions (e.g., holding his or her arm up, vertically and/or
hanging down). While not wishing to be bound by theory, it is
believed that these signal artifacts can arise because femoral
veins are relatively small (e.g., 1-2 mm diameter), and in some
circumstances an inserted catheter can block the flow of at least
some incoming blood, such that the incoming blood is "diverted"
around the implantation site by flowing through adjacent
alternative veins and/or capillaries. As a result, the blood in the
vein containing the catheter can be diluted for a period of time
(e.g., after flushing), which can lead to diluted analyte values,
which appear as signal artifacts. As time passes, the dilution of
the sample by the saline flush dissipates and undiluted blood
samples are collected, which leads to termination of the signal
artifact(s). The way the host holds his or her arm can affect the
length of time required for the signal artifact to dissipate. For
example, in some embodiments, if the host holds his or her arm at
chest level, the vein is filled by blood at a first rate, and the
sample dilution is dissipated within a first time period. If the
host holds his or her arm down low, the blood flows through the
vein at a second rate that is faster than the first rate, and the
dilution is relieved sooner (e.g., within a second time period that
is shorter than the first time period). Conversely, if the host
raises his or her arm over his or her head, the blood flows into
the vein at a third rate that is slower than the first rate; which
results in the dilution dissipating within a third period of time
that is longer than the first period of time.
[0911] In some embodiments, the signal artifacts resulting from
blocking of the vein at the site of catheter implantation and
subsequent sample dilution can be substantially eliminated (or
reduced/shortened) by reducing the volume of 0 mg/dl solution used
to wash away the 100-mg/dl calibration solution, depending upon the
volume of the 100 mg/dl calibration solution used to calibrate the
sensor. For example, in some embodiments a 0.5.times., 1.times.,
2.times., 3.times., 4.times., 5.times., 6.times., 7.times.,
8.times., 9.times., 10.times. (or greater) volume of the 0-mg/dl
solution can be used to sufficiently wash out the volume 100 mg/dl
calibration solution. In some embodiments, wherein a sufficiently
small volume of 100 mg/dl solution is used during calibration, the
flushing can be done at the KVO rate. In some embodiments, signal
artifacts are prevented by using smaller volumes of
calibration/wash fluids but switching more frequently between the
fluids.
[0912] Maintaining Patency During a Sensor Session
[0913] In some embodiments, the analyte sensor is implanted in the
host (e.g., via a vascular access device) for an extended period of
time. For example, in some embodiments, a sensor session can last
3, 5, 7, 10, 21, 30 or more days. As used herein, the term "sensor
session" is a broad term and refers without limitation to the
period of time of sensor is applied to (e.g., implanted in) the
host and is being used to obtain sensor values. For example, in
some embodiments, a sensor session extends from the time of sensor
(e.g., including implanting the vascular access device)
implantation to when the sensor is removed. During this period of
time, the vein's condition can deteriorate, such that vein and/or
vascular access device is no longer patent (e.g., freely open, not
occluded), and the system can no longer function optimally. While
not wishing to be bound by theory, it is believed that patency can
be substantially maintained during a sensor session by metering a
reference/calibration solution through the vascular access device a
sufficient amount of time (e.g., a percentage of the duration of
the sensor session). As used herein, the phrase "a sufficient
amount" is a broad term and refers without limitation to an amount
that provides a desired function. For example, a sufficient amount
can be a sufficient amount of time, a sufficient amount of fluid
volume, and the like. In some embodiments, a sufficient amount can
be expressed numerically, such as a percent (%), a volume, a
weight, a period of time (e.g., minutes, hours, days, months), and
the like. For example, in some embodiments, the flow control device
is configured to meter a sufficient amount of a reference solution
(e.g., through the vascular access device) such that the analyte
sensor contacts the reference solution at least about 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the time during a
sensor session. It is generally preferred that the analyte sensor
contacts the reference solution from about 50% to about 80%, 85%,
90% or 95% of the time during a sensor session In some embodiments,
the sensor is located in or on the vascular access device and the
flow control device meters the reference solution through the
vascular access device for a sufficient amount of time (e.g., a
portion of the sensor session), with a sufficient flow rate (e.g.,
from about 0.05 ml/min to about 0.5 ml/min, preferably about 0.1
ml/min) that the vascular access device remains patent during a
sensor session.
[0914] Advantageously, the flow rate is sufficient to maintain a
patent vessel without infusing excess fluid. In a preferred
embodiment, the vascular access device remains patent during a
sensor session of at least about 1, 3, 5, 7, 10, 15, 20, 25, or 30
days, or longer. In one exemplary embodiment, the flow control
device is configured to meter the reference solution through the
vascular access device for at least about 50% of a sensor session,
at a flow rate from about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2,
0.1, 0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009,
0.008, 0.007, 0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/min or
less to about 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or
2.0 ml/min or more, such that the vascular access device remains
patent during a sensor session of at least about 5 days. In another
exemplary embodiment, the flow control device is configured to
meter the reference solution through the vascular access device for
at least about 65% of a sensor session, at a flow rate from about
0.001 ml/min to about 2.0 ml/min, such that the vascular access
device remains patent during a sensor session of between about 5
days and about 30 days. In still another exemplary embodiment, the
flow control device is configured to meter the reference solution
through the vascular access device for between about 50% and about
80% of a sensor session, at a flow rate from about 0.001 ml/min to
about 2.0 ml/min, such that the vascular access device remains
patent during a sensor session of at least about 30 days.
[0915] Preventing Sensor Biofouling During a Sensor Session
[0916] As discussed above, sensor sessions can last from about 3
days to 30 or more days. During this period of time, the sensor is
repeatedly exposed to (contacted with) a bodily fluid (e.g.,
blood). In some circumstances, during sensor exposure to blood,
some blood components/material, such as but not limited to
proteins, lipids, carbohydrates and cells, can "stick" to the
sensor, such that a layer of this material coats at least part of
the sensor and the sensor can no longer function accurately. This
process of blood components sticking to the sensor and disrupting
the sensor's function is generally referred to as "biofouling."
While not wishing to be bound by theory, it is believed that
biofouling can be substantially reduced and/or eliminated by
limiting the length of time the sensor is exposed to blood and/or
by maintaining the sensor in a reference solution (or saline) a
substantial portion of the sensor session, whereby sensor accuracy
is maintained throughout the sensor session. Washing the sensor is
described in detail in the section entitled "Maintaining Patency
During A Sensor Session."
[0917] As a non-limiting example, in some embodiments, the flow
control device is configured to meter the reference solution, such
that the reference solution contacts the sensor a substantial
amount of time such that biofouling does not occur for at least
about 3 days of sensor use. For example, the sensor can be
contacted with the reference solution about 50%, 60%, 70%, 80%,
90%, or 95% of the sensor session duration. In preferred
embodiments, the system is configured such that biofouling does not
occur for at least about 7, 10, 21, 30 or more days of sensor
use.
[0918] In one exemplary embodiment, wherein the sensor is located
in or on a vascular access device, the system includes a flow
control device configured to meter a reference solution through the
vascular access device for a sufficient amount of time and with a
sufficient flow rate that substantially no biofouling of the sensor
occurs during a sensor session of at least about 3 days. For
example, in some embodiments, the flow control device meters the
reference solution through the vascular access device for at least
about 50% of a sensor session, at a flow rate from about 0.001
ml/min to about 2.0 ml/min, such that substantially no biofouling
of the sensor occurs during a sensor session of at least about 5
days. In another exemplary embodiment, the flow control device
meters the reference solution through the vascular access device
for at least about 65% of a sensor session, at a flow rate from
about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.08,
0.07, 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.009, 0.008, 0.007,
0.006, 0.005, 0.004, 0.003, 0.002 or 0.001 ml/min or less to about
1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.0 ml/min or
more, such that substantially no biofouling of the sensor occurs
during a sensor session of between about 5 days and about 30 days.
In still another exemplary embodiment, the flow control device
meters the reference solution through the vascular access device
for between about 50% and about 80% of a sensor session, at a flow
rate from about 0.001 ml/min to about 2.0 ml/min, such that
substantially no biofouling of the sensor occurs during a sensor
session of at least about 30 days.
[0919] Alternative Flow Control Device Configurations
[0920] As disclosed above, the flow control device 604 can be
configured a variety of ways, which can require modifications to
one or more of the steps of operation described above. For example,
in some embodiments, the flow control device 604 can be configured
to include a simple pinch valve, wherein the valve can be
configured to open, close or partially open. In some embodiments,
the flow control device 604 can be configured to include a
non-linear rolling pinch valve, wherein the roller can move back
and forth between opened, closed and partially opened positions,
for example.
[0921] In some embodiments, the flow control device 604 can include
one roller 802 (e.g., first structure) attached to an axle 804 and
configured to press against a curved surface 806 (e.g., second
structure), such that when the roller 802 is pressing against the
curved surface 806 at or between positions 810 and 812, the tubing
606 is pinched completely closed and the flow control device 604
moves the roller 802 forward (e.g., toward the host). In one
exemplary embodiment, the flow control device 604 can be configured
to perform step one (above, contacting the sensor 14 with solution
602a) by moving the roller 802 forward (e.g., rotating from
position 810 to 812, see FIG. 8A), thereby causing solution 602a to
flow over the sensor 14. In some embodiments, the flow control
device 604 is configured to perform step two (contacting the sensor
14 with sample) by moving the roller 802 backwards (e.g., rotating
from position 812 to 810, see FIG. 8B), thereby causing blood 814
to enter the catheter 12 and contact the sensor 14. Additionally,
the flow control device 604 can be configured to perform a wash or
KVO step by moving the roller 802 forward (from position 810) past
position 812 and around the axle 804 until position 810 is again
reached a plurality of times sequentially (e.g., see FIG. 8C). In a
further example, the flow control device 604 includes two, three or
more rollers 802 arranged about axle 804, such as by attachment to
an oblong body attached to the axle. In some embodiments, the flow
control device includes a plurality of rollers arranged about the
axle, wherein the flow control device performs KVO by rotating the
rollers about the axle a plurality of times, to substantially
continuously push (e.g., for a period of time) the solution forward
into the host.
[0922] In one alternative embodiment, back flow is substantially
stopped, blocked and/or prevented by incorporation of a one-way,
pressure-controlled valve into the system, such as at or adjacent
to the catheter or sensor connector, whereby fluid can flow into
the host only when fluid pressure (e.g., head pressure) is applied
to the reservoir-side of the valve. In other words, fluid can only
flow in the direction of the host (e.g., toward the host), not
backwards towards the reservoir. In some embodiments, the valve is
a two-way valve configured such that the pressure required to open
the valve is greater than the venous pressure, such that back flow
is substantially prevented.
[0923] The preferred embodiments provide several advantages over
prior art devices. Advantageously, the movement of the solution
602a and sample occur at a metered rate and are unaffected by
changes in head pressure, such as but not limited to when the host
elevates his or her arm or gets up to move around. Also, sample
loss to the host is minimized, first by returning all collected
samples to the host; and second by substantially preventing
back-flow from the host (e.g., into the tubing or reservoir) with a
"hard stop" (e.g., a point beyond which the flow control device
cannot move fluid into or out of the host). For example, in one
preferred embodiment, the flow control device can be configured to
deliver no more than 25-ml of solution to the host per hour. In
another exemplary embodiment, the flow control device can be
configured to draw back no more than 100 .mu.l of blood at any
time. Advantageously, the flow rate of solution 602a and sample 814
is carefully controlled, such that both the sample 814 and the
solution 602a remain substantially undiluted. Additionally, the
solution 602a warms to the host's local body temperature, such that
the integrated sensor system 600 is substantially unaffected by
temperature coefficient and sensor 14 accuracy is increased.
[0924] FIGS. 10A through 10D illustrate one exemplary embodiment of
a flow control device 604 configured and arranged for use with a
vascular access device (e.g., catheter and/or fluid coupler) and
analyte sensor, such as those described elsewhere herein. The flow
control device includes a groove 803 configured to receive the
tubing assembly therein 606a. In some embodiments, the groove 803
is configured and arranged to receive the tubing (of the tubing
assembly) in a substantially straight configuration. The groove 803
intersects with a valve roller mechanism, which includes an oblong
body comprising two rollers 802 (e.g., corresponding to the first
structure 802, which is attached to axle 804 of the embodiment
shown in FIGS. 8A-8C) and a compression surface 806 (e.g.,
corresponds to the second structure 806 of the embodiment shown in
FIGS. 8A-8C). The valve includes at least two valve positions, a
gravity flow valve position and a controlled-flow valve position.
FIG. 10C illustrates one embodiment of the gravity flow valve
position, in which the rollers 802 are positioned such that they do
not compress, pinch and/or occlude the tubing, such that fluid
flowing from the IV bag can flow freely through the tubing 606b in
the valve. At gravity flow, the rate of fluid flow through tubing
606b is from about 600-ml/hr (e.g., about 10 ml/min) to about
700-ml/hr (e.g., about 1.2 ml/min), depending upon the height of
the IV bag 602.
[0925] FIG. 10D illustrates one embodiment of the controlled-flow
valve position, in which a roller 802 is positioned such that the
tubing 606b (of the tubing assembly) is pinched between the roller
802 and compression surface 806 (e.g., pinch point 808 exists),
such that movement of fluid through the valve is controlled by the
rotation of the oblong body (e.g., to which the roller is attached)
on its axle. In the controlled flow position, the valve is
configured and arranged to move fluid forward and/or backward at
various rates, depending upon the speed and direction of oblong
body rotation on the axle. Flow rates can be positive (e.g.,
infusing fluid) or negative (e.g., drawing back fluid/blood) and
can range from about -10.0, -9.0, -8.0, -7.0, -6.0, -5.0, -4.0,
-3.0, -2.0, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2,
-0.1, -0.05, -0.01, 0.0, 0.01, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6,
0.7, 0.8, 0.9, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, 10.0
ml/hr to about 20.0, 30.0, 40.0, 50.0, 60.0, 70.0, 80.0, 90.0,
100.0, 110.0, 130.0, 150.0, 175.0, 200.0, 225.0, 250.0, 275.0,
300.0, 350.0, 400.0, or 450.0 ml/hr or more. Useful flow rates and
valve movement between the gravity flow and controlled-flow valve
positions are described in greater detail elsewhere herein with
reference to FIG. 10E.
[0926] The valve is configured to receive the tubing 606b (e.g., of
the tubing assembly 606a), such as via groove 803 (e.g., tubing
path or channel). One skilled in the art understands that while
FIGS. 10A-10D illustrate groove 803 running from the top of the
valve to the bottom (e.g., on the face or front of the device),
additional configurations are possible. Namely, the groove can be
located in any direction or orientation along any surface of the
device (e.g., top, bottom, sides), or the groove can be enclosed
within the device, such as within a housing configured cover,
supports and/or limit access to the valve, a portion of the tubing,
and/or accessory devices. For example, in some embodiments, the
valve is located within a housing, such that the valve and the
tubing assembly are accessed via a door. The housing can include
one or more orifices, such that the tubing can intersect (e.g.,
pass through) a wall of the housing and be installed into the valve
within the housing. In some embodiments, the door includes a
locking mechanism, such as but not limited to a mechanical key or
electronics code key (e.g., electronically, such as such as to
prevent tampering with the device).
[0927] The valve is configured for uni-directional, releasable
installation of the tubing assembly 606a (also referred to herein
as "tubing set"), such that the tubing assembly's elastic central
portion 606b (e.g., tubing) is received by the groove and the
tubing's fluid connectors 606c, 606d are disposed at opposite ends
of the groove, in some embodiments. In some embodiments, the groove
is sized to be somewhat longer than the central portion of the
tubing assembly, such that the tubing (of the tubing assembly) must
be stretched (e.g., by grasping the connectors and pulling in
opposite directions) prior to and/or during installation into the
channel/groove. After installation, the connector ends are
released, such that the tubing relaxes. However, the tubing remains
stretched (e.g., relative to its un-stretched state prior to
installation) after installation. Maintaining the tubing in a
stretched state can help maintain the tubing assembly within the
valve without the tubing moving, twisting, kinking or falling out
of the valve. The tubing assembly is configured for fluid
communication with an IV bag (e.g., fluid reservoir 602), such as
via the first connector 606c, and with the circulatory system of
the host, such as via fluid connection of the second connector 606d
to a catheter implanted in the host.
[0928] In some embodiments, the valve is configured and arranged to
receive the tubing assembly in only one orientation. For example,
in some embodiments, the valve and the tubing assembly are
configured and arranged to releasably interlock such that a portion
of the valve mechanically interlocks with a portion of the tubing
assembly. For example, in some embodiments, the valve includes the
first portion of a mechanical interlock and the tubing assembly
includes the second portion of the mechanical interlock. For
example, in FIG. 10A, the valve includes a female interconnection
809 sized and shaped to releasably receive and engage the tubing
assembly's second connector 606d (which in this embodiment includes
rectangular wings that project from a female Leur connector). As is
appreciated by one skilled in the art, the system can be configured
such that the mechanical interlock is located at either end of the
groove 803 (e.g., such that connector 602 forms a portion of the
mechanical interlock, instead of connector 606d) or at some point
in between. Advantageously, the mechanical interlock reinforces
uni-directional installation of the tubing assembly, as well as
helping to maintain the tubing within the valve in the correct
configuration.
[0929] In some embodiments, the mechanical interlock is configured
to engage a particular vascular access device (e.g., a specific
type of catheter), wherein the mechanical interlock and/or the
vascular access device are configured and arranged to provide
additional structural and/or electronic identification information,
to ensure and/or to promote the use of the correct vascular access
device (e.g., catheter, fluid coupler) and/or to enable the correct
selection of a flow profile associated with the vascular access
device. For example, in one embodiment, the mechanical interlock is
configured and arranged to identify (to the flow control device)
the type of vascular access device and/or sensor being used (such
as for identification of the flow profile that corresponds with the
selected catheter). In some embodiments, the mechanical interlock
provides identification information to the flow control device,
wherein the identification information is associated with the
vascular access device and a corresponding flow profile. In
preferred embodiments, the identification information is provided
automatically, such as by a mechanical structure of the vascular
access device. In some embodiments, the identification information
is provided by electronics associated with the vascular access
device. For example, in one embodiment, the catheter includes the
electronics that provide the identification information. In another
embodiment, the fluid coupler includes the electronics that provide
the identification information. In one exemplary embodiment, the
system is configured to select a flow profile associated with a
mechanical interlock (e.g., the identification information), when
the mechanical interlock is engaged (e.g., the vascular access
device is connected to the tubing assembly and/or the flow control
device). Additional a mechanical interlock between the second end
of the tubing assembly and the vascular access device is configured
and arranged to prevent twisting of the connection between the
tubing assembly and the vascular access device.
[0930] In some embodiments, uni-directional tubing installation is
important for aligning functional portions of the valve with
functional portions of the tubing assembly. For example the tubing
assembly includes an elastic tubing portion configured to be
manipulated by the valve (e.g., pinched, etc.). In another example,
the valve can include one or more functional elements, such as but
not limited to a bubble detector 805 (located along groove 803 and
configured and arranged to detect bubbles in the tubing 606b) and
an electronic solenoid 807 (e.g., configured to align with the free
flow mitigation device 606e of the tubing and to open the free flow
mitigation device, see "Free Flow Mitigation").
[0931] Referring now to FIGS. 10C-10D, in some embodiments, the
flow control device includes a flow profile comprising two valve
positions, a gravity flow position and a controlled flow position.
Flow profiles are described in detail with respect to FIG. 10E. In
preferred embodiments, the valve is configured and arranged to move
between the gravity flow and controlled flow valve positions, such
that when the valve is in the gravity flow position, tubing
received therein is in a substantially straight (e.g., linear)
configuration and when the valve is in the controlled flow
positions the tubing received therein is in a substantially
non-linear configuration. As a non-limiting example, FIG. 10C
illustrates a gravity flow position, in which the valve roller
(e.g. the first structure 802, a roller attached to an oblong
rotating member or body configured to engage curved surface 806) is
oriented (e.g., positioned) such that there is no pinch point in
the tubing (e.g., the tubing is not compressed between the first
and second structures). In this embodiment, the tubing is in a
substantially straight (e.g., un-bent, unpinched, and/or not
occluded) configuration when the valve is in the gravity flow
position. In the gravity flow position, IV fluid can flow freely
through the vascular access device and into the host,
simultaneously flushing and/or washing the analyte sensor. FIG. 10D
illustrates the valve in a controlled flow position. In the
controlled flow position, the rotating member 802 is rotated on its
axle to an orientation such that the tubing 606b is non-linear
(e.g., curved, bent) and a pinch point 808 (e.g., between the
rotating member 802 and the compression surface 806) prevents fluid
flow. The valve is configured to rotate the roller valve on an
axle, such that the pinch point can be moved along the compression
surface. Thus, the flow control device moves through a plurality of
controlled flow positions. Movement of the valve is similar to the
valve movements described with reference to FIGS. 8A-8C.
Accordingly, when the tubing is in a bent configuration, the pinch
point 808 is pushed forward (e.g., along surface 806) as the
rotating member moves forward, and such that an amount of fluid is
pushed forward (e.g., infusion fluid, calibrant, sample) through
the tubing, as described with reference to FIG. 8A. Similarly, when
the tubing is in a bent configuration, the pinch point 808 is
pushed backwards (e.g., along surface 806) as the rotating member
moves in reverse, such that an amount of fluid is drawn back (e.g.,
infusion fluid, calibrant, sample) through the tubing, such that a
sample is drawn back into the vascular access device and the
analyte sensor is bathed in the sample.
[0932] FIG. 10E is a graph illustrating an exemplary flow profile,
in one embodiment. In preferred embodiments, the flow control
device (e.g., the valve) includes a flow profile that is configured
and arranged to direct the movements of the flow control device
(e.g., between the free flow and controlled flow valve positions,
see FIGS. 10C-10D), such that the analyte sensor is alternately
bathed in samples and washed by the infusate (e.g., IV fluid,
calibrant solution, a medicament solution, and the like). Referring
to the exemplary flow profile depicted in FIG. 10E, time is shown
on the X-axis and flow rate (e.g., the rate of fluid being moved
through the valve) is shown on the Y-axis. Because this is a
generic flow profile, for discussion purposes only, the Y-axis is
relative and thus has no 0-ml/hr flow rate depicted. A specific
flow profile can include a 0-ml/hr flow rate, as well as positive
(e.g., valve moving forward) and negative (e.g., valve moving
backwards) flow rates. The flow profile includes one or more phases
(e.g., phases X, Y and Z); wherein each phase is configured to
infuse an amount of fluid, to draw back an amount of sample and/or
to hold an amount of fluid (e.g., infusion fluid and/or drawn-back
sample) stagnant (e.g., substantially still). In general, a phase
is associated with a function, such as but not limited to drawing
back a sample (e.g., blood) such that the analyte sensor is bathed
in the sample, returning the used sample to the host, washing the
analyte sensor (e.g., with solution), calibrating the sensor,
maintaining vessel patency, KVO, infusing a hydration fluid,
infusing an amount of medicament (e.g., responsive to analyte
sensor data and/or to a criterion and/or protocol), and the like.
In general, a phase of the flow profile can include one or more
flow rates, each of which can last various periods of time. A rate
can be selected depending upon the function of the phase of the
flow profile, the content of the infusion fluid, the size of the
vascular access device (e.g., catheter size, sample size, etc.), a
medication protocols, and the like.
[0933] As a non-limiting example, the flow profile depicted in FIG.
10E includes three phases (e.g., X, Y, and Z). Phase X includes two
flow rates, Rate A and gravity flow (GF). Phase Y includes a second
rate (Rate B), which is lower (e.g., slower) than Rate A. Phase Z
contains a third rate (Rate C), which is lower than both Rates A
and B. At Rates A, B and C, the valve is in a controlled flow valve
position. When the valve is in a controlled flow position, it can
be stationary (e.g., 0-ml/hr flow rate) or it can move through a
plurality of positions in which the tubing is pinched between the
roller 802 and the compression surface 806. While not wishing to be
bound by theory, one can consider an infinite number of controlled
flow positions to exist, wherein the valve creates pinch point 808
by compressing the tubing between the roller 802 and compression
surface 806. Similarly, an infinite number of pinch points can
exist along the compression surface, provided that the valve is in
a controlled flow position. The valve is configured to move at a
plurality of speeds, such that the valve can move the pinch point
at a plurality of speeds (faster/slower), such that the desired
(e.g., programmed and/or re-programmed) flow rates are achieved.
For example, fluid can be infused at rates from about 0.0, 0.001,
0.01, 0.1, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0,
6.0, 7.0, 8.0, 9.0, 10.0 ml/hr to about 20.0, 30.0, 40.0, 50.0,
60.0, 70.0, 80.0, 90.0, 100.0, 110.0, 130.0, 150.0, 175.0, 200.0,
225.0, 250.0, 275.0, 300.0, 350.0, 400.0, or 450.0 ml/hr or more.
In another example, sample can be drawn back at rates from about
-10.0, -9.0, -8.0, -7.0, -6.0, -5.0, -4.0, -3.0 ml/hr to about
-2.0, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2, -0.1,
-0.05, -0.01 or -0.001 ml/hr or less. In some embodiments, when the
valve is in the controlled flow position, the flow rate is from
about 0.5-ml/hour to about 4.0-ml/hr. In some embodiments, a phase
of the flow profile can include two, three, four or more rates. In
some embodiments, a phase can include a period of gravity flow
(e.g., GF), during which the valve is moved to the gravity flow
position, which is discussed in greater detail below. In some
embodiments, the one or more rates are optimized to achieve the
function of the phase relative to a medical protocol. For example,
during a wash phase, a slower flow rate can be used if the infusion
solution contains heparin, as compared to the flow rate necessary
to sufficiently clean the sensor of blood cells when a
non-heparinized infusion solution is used. As another example, if
the infusion solution contains a medicament, the flow rate of a
wash phase can be selected to optimize sensor cleaning while still
infusing the desired amount of medicament into the host. In still
another example, a slower flow rate can be chosen to flush the
sensor and return the sample to a neonatal host, due to the small
lumen size of the catheters used in such tiny hosts, such that, for
example, excessive amounts of fluid are not infused into the host.
In yet another example, during a calibration phase, the calibrant
can be slowly infused (e.g. prior to and/or during measurement of
the calibration solution), such that the temperature of the
calibration fluid equilibrates with the host's body temperature, as
described elsewhere herein. In still another example, during a
measurement phase, a sample can be drawn back at a rate selected to
maintain the temperature of the sample, to prevent rupture of blood
cells within the sample, and/or to optimize sensor function.
[0934] The flow profile can include periods of gravity flow (GF),
during which the valve is in the gravity flow valve position and
fluid 602a can flow freely through the valve (e.g., through the
tubing received by the valve). The rate of gravity flow is
dependent upon the affect of gravity on the infusion fluid, and
thus depends in part on the height of the bag 602. For example, the
bag can be located relatively higher or lower, with respect to the
valve, the floor and/or the host. If the bag is higher, the flow
rate will be relatively faster. If the bag is lower, the flow rate
will be relatively slower. In some embodiments, gravity flow rates
range from about 600, 630 or 650-ml/hour to about 670 or
700-ml/hour or more. In some embodiments, when the valve is in the
gravity flow valve position, the flow rate is at least about
600-ml/hr. In some embodiments, the system is configured such that
the analyte sensor is flushed (e.g., washed, cleaned, cleaned) by
the solution when the valve is in the gravity flow valve position.
For example, in some embodiments, gravity flow removes blood cells
or other blood components from the sensor and/or the lumen of the
vascular access device more efficiently that other (e.g., lower)
flow rates.
[0935] In some embodiments, washing of the sensor is optimized by
setting a ratio of gravity flow rate to controlled flow rate, such
as via programming the flow profile to provide the flow rates. For
example, in some embodiments, the ratio of gravity flow (e.g., a
first flow rate) to controlled flow (e.g., a second flow rate) is
at least about 10:1, wherein, the rate of gravity flow lasts
10-times greater than the controlled flow rate. In some
embodiments, the ratio of the gravity flow rate to the controlled
flow rate is at least about 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or
9:1. In some embodiments, the ratio of the gravity flow rate to the
controlled flow rate is from at least about 12:1, 15:1, 20:1, 30:1,
40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or 100:1 to at least about
125:1, 150:1, 175:1, 200:1, 250:1, 300:1, 350:1, 400:1, 450:1, or
500:1 or greater. In some embodiments, the ratio of the gravity
flow rate to the controlled flow rate is optimized for sensor
washing. For example, the ratio is optimized such that the washed
sensor's measurement of the current sample is substantially
unaffected by the presence of components of the previous blood
sample. For example, in some embodiment, the optimal ratio of the
gravity flow rate to the controlled flow rate, for sensor washing,
is 10:1. In some embodiments, the optimal ratio (of gravity flow to
controlled flow) for sensor washing is at least about 2:1, 3:1,
4:1, 5:1, 6:1, 7:1, 8:1 or 9:1. In some embodiments, the ratio of
the gravity flow rate to the controlled flow rate is from at least
about 12:1, 15:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1 or
100:1 to at least about 125:1, 150:1, 175:1, 200:1, 250:1, 300:1,
350:1, 400:1, 450:1, or 500:1 or greater. In some embodiments, a
period of gravity flow is included in a phase of the flow profile,
such as a wash or flush phase, or in a phase configured to infuse a
programmed amount of infusion solution (e.g., for hydration, for
nutrition and/or to deliver an amount of medicament). In some
embodiments, the flow profile is configured to cycle between two or
more flow rate ratios. In some embodiments, the ratio of flow rates
is associated with the configuration of the system. For example, a
system configuration for use in an adult host will have different
flow profile requirements than a system configured for use in a
pediatric host. In another example, a system configured access of
the circulatory system via an artery will have different flow
profile requirements than a system configured for access via a
vein. In yet another example, a system having the sensor extend
into a catheter's lumen may be have different flow profile
requirements than a system having a sensor located in a fluid
coupler.
[0936] Returning to FIG. 10E, the flow profile can be configured
differently, depending upon the system configuration, the type of
host, and the like. For example, the flow profile can include more
or fewer phases. In another example, Phase X can include one or
more additional flow rates, or it could consist of only Rate A or
only GF. In another example, Rate B can be slower or faster than
depicted, including even slower than Rate C or greater than Rate A.
In another example, Phase Y can include additional periods of
faster and/or slower rates and/or one or more periods of GF. Rate C
can be even slower, or it could be faster. If Rate C is a negative
rate, then sample is being drawn back and can be drawn back at
slower (less negative) or faster (more negative) speeds. In another
example, a phase can include two or more flow rates that are
alternated intermittently and/or periodically throughout the phase.
In yet another example, a phase can include a flow rate of about
0.0 ml/min, wherein the fluid and/or sample is held substantially
stagnant for a period of time.
[0937] In some embodiments, at least a portion of a flow profile
can be repeated. For example, two or more phases can be repeated
for a period of time, such as but not limited to a period of time
lasting from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours to
about 0.75, 1, 2, 3, 4 or more days. In some embodiments, the two
or more phases of the flow profile are repeated until a criterion
is met and/or exceeded (e.g., until a certain period of time has
passed, until an amount of medicament is infused, until the host's
blood analyte level falls within a preprogrammed range of
concentrations, until a caretaker responds to an alarm by pressing
a button on the user interface, and the like). In some embodiments,
all of the phases of the flow profile are repeated, such as in a
cyclical manner, such as until the end of the sensor session (e.g.,
when the sensor is removed from the host and/or the system is
turned off). In some embodiments, the flow profile is configured to
be paused and/or interrupted, such as during transfer of the host
from his hospital room to another location for a procedure, for
example.
[0938] In some embodiments, the flow profile is configured to be
responsive to the analyte level measured/generated by the sensor.
For example, the flow profile can be configured to use one or more
optional phases, which can include one or more alternative flow
rates, when the analyte measured meets/exceeds a criterion. For
example, in some embodiments, the infusion solution includes a
medicament. In some embodiments, the flow profile is configured to
meter the flow of the medicament solution based at least in part on
a measured analyte concentration. In one exemplary embodiment, the
sensor includes a glucose sensor, the IV solution contains insulin,
and the flow profile is configured to infuse an amount of the
insulin solution in response to the host's glucose level. For
example, the flow profile can be configured to infuse a low amount
of insulin continuously (e.g., a basal amount) and when the host's
blood glucose exceeds a programmed range, the flow profile can
increase the rate of infusion for a period of time, such as until
the host's glucose returns to the range (e.g., a bolus amount). In
some embodiments, the amount of medicament (e.g., the insulin
solution) to be infused is calculated by the processor module,
responsive to the sensor data. In some embodiments, the processor
module includes at least a portion of the flow profile. In some
embodiments, the flow profile includes an optional phase, such as
but not limited to an infusion phase, configured to infuse an
amount of medicament. For example, in some embodiments, the
processor module includes a medicament infusion phase configured to
infuse an amount of insulin sufficient to return the host's blood
glucose to a programmed range (e.g., between 80-120 mg/dl glucose).
In some exemplary embodiments, the flow profile can be programmed
(e.g., re-programmed), such as by the processor module (e.g.,
responsive to at least one criterion), such that a medicament
infusion phase is added to the flow profile for one or more cycles.
In some embodiments, the flow profile includes selectable
sub-profiles, which can be automatically selected by the flow
profile responsive to one or more criteria and/or selectable and/or
programmable by a caretaker. In some embodiments, the flow profile
includes a menu of selectable flow profiles (e.g., two or more),
from which a user can select one to use when applying the system to
a host (e.g., installation, set up). For example, in some
embodiments, a user can select the flow profile to use from the
menu, depending upon host physical properties, a drug to be
infused, certain medical protocols, and the like.
[0939] As described in the section entitled "Fluids," in some
embodiments the infusion solution is a saline solution formulated
for infusion into the host. In some embodiments, the infusion
solution can contain an amount of the calibrant. For example, if
the sensor is a glucose sensor, the infusion solution can contain
an amount of glucose (e.g., 50, 75, 100, 125, 150, 175, or 200
mg/dl glucose or more) suitable for calibrating the glucose sensor.
This type of solution may be referred to as a "calibration
solution." In some embodiments, the medicament solution can include
a calibrant. For example, if the sensor is a glucose sensor and the
medicament is insulin, the insulin solution can also contain
glucose. Alternatively or additionally, the calibration solution
and the medicament solutions can be provided separately, such at in
separate IV bags. Accordingly, in some embodiments, the system is
configured to switch some one IV bag to the other (e.g., from the
calibration solution (e.g., glucose) to the medicament solution
(e.g., insulin) and vice versa) accordingly to the flow profile. In
other embodiments, the system includes as mixing valve configured
and arranged to mix the medicament solution and the calibrant
solution, wherein a ratio of medicament solution to calibrant
solution is based at least in part on a measured analyte
concentration. For example, if the host's blood glucose exceeds the
programmed range, then the flow profile can respond by directing
mixing an amount of the insulin solution into the calibration
solution being infused, wherein the amount of insulin is sufficient
to return the host's glucose to the programmed range. In some
embodiments, the flow control device is further configured and
arranged for a piggyback connection with a medicament delivery
device, such as a bedside or ambulatory infusion pump. In preferred
embodiments, the piggyback connection includes at least one check
valve. Check valves can be configured to provide a variety of
functions. For example, in some embodiments, the check valve is
configured to prevent backflow into the piggybacked medicament
delivery device, such as flow of calibration solution into the
medicament delivery device's medicament reservoir. In other
embodiments, the check valve is configured to prevent inadvertent
draining of the medicament reservoir into the host, such as when
the system is shut off. Descriptions of some medicament infusion
devices suitable to piggyback with the present system can be found
in U.S. Pat. Nos. 4,685,903, 4,898,578, 4,925,444, 5,158,437,
5,219,279, 5,207,642, 5,248,300, 5,321,392, 5,496,273, 5,522,798,
5,482,446, 5,547,470, 5,551,850, 5,630,710, 5,681,285, 5,685,844,
5,745,378, 6,231,320, 6,231,560, 6,269,340, 6,544,229, 6,648,821,
6,817,990, 6,692,457, 6,985,870, 7,018,361, 7,109,878, 7,204,823,
7,402,153, 7,417,729, U.S. Patent Publication No.
US-2007-0060871-A1, U.S. Patent Publication No. US-2007-0112298-A1,
U.S. Patent Publication No. US-2007-0213657-A1, U.S. Patent
Publication No. US-2007-0299389-A1, U.S. Patent Publication No.
US-2008-0033357-A1, U.S. Patent Publication No. US-2008-0097326-A1,
U.S. Patent Publication No. US-2008-0103447-A1, U.S. Patent
Publication No. US-2008-0154177-A1, U.S. Patent Publication No.
US-2008-0147050-A1, U.S. Patent Publication No. US-2008-0161753-A1,
and U.S. Patent Publication No. US-2008-0200897-A1, each of which
is incorporated herein by reference in its entirety.
[0940] As described herein, in some embodiments, the flow control
device includes an electronic solenoid 805 configured to operate a
free flow mitigation device 606e (e.g., a spring-clip occluder
included in the tubing assembly 606a). A free flow mitigation
device is configured and arranged to prevent inadvertent free flow
of IV solution into the host, such as during tubing installation
and removal, or during power interruption to the system. The flow
control device and tubing assembly are configured and arranged such
that they are functionally engaged after the tubing is installed in
the vascular access device. For example, in FIG. 10A, the free flow
mitigation device 606e and the electronic solenoid 805 are aligned
such that the solenoid can bias (e.g., activate) the spring clip
occluder in a non-occluded (e.g., un-pinched, opened) position,
when the system is in operation. The spring clip occluder is
configured and arranged to be engaged by an electronic solenoid 805
located in the flow control device. In preferred embodiments, the
electronic solenoid 807 is configured and arranged such that free
flow mitigation device returns to an occluded position when power
is removed, such as when the system is turned off on in the event
of a power outage. In preferred embodiments, the system configured
and arranged to control the free flow mitigation device
electronically, such as but not limited to by the flow profile. For
example, in one embodiment, after system installation and/or
initiation, the flow profile electronically controls the electronic
solenoid to maintain the spring clip occluder in an opened
position. In another embodiment, the flow profile directs the
solenoid to activate (e.g., open, biased in the non-occluded
position) the free flow mitigation device during solution infusion
and/or sample drawback, and to deactivate (e.g., closed, bias in
the occluded position) the free flow mitigation device if the
system is paused and/or the system is switched off. In still
another embodiment, the flow profile includes a phase with a
0-ml/hr (or 0-ml/min) flow rate, and the flow profile
electronically directs the solenoid to deactivate the free flow
mitigation device during this phase, and activation (e.g.,
reactivation) of the free flow mitigation device during the other
phases of the flow profile. In some embodiments, the flow profile
is configured to deactivate the free flow mitigation device (e.g.,
via the electronic solenoid) in response to a fail-safe, such as
but not limited to in response to a fail-safe programmed to handle
a fluidics problem or a sensor failure. Fail-safes are described in
detail elsewhere herein.
[0941] In some embodiments, the system is configured to infuse an
amount of medicament, responsive to the analyte sensor data. In one
exemplary embodiment, the system includes a continuous glucose
sensor and processor module including a flow profile (e.g.,
programming) configured for infusion of an amount of an insulin
solution (e.g., such that a calculated amount of insulin is
infused) in response to the host's glucose concentration. For
example, processor module is configured to and/or includes
programming that processes the continuous glucose sensor data,
whereby the host's glucose level is determined in real time. In
preferred embodiments, the processor module is configured to
calculate the volume of insulin solution to be infused, such as if
the host's blood glucose exceeds a predetermined threshold (e.g.,
the host is hyperglycemic; e.g., glucose above 120 mg/dl, 130
mg/dl, 140 mg/dl, 150 mg/dl, 160 mg/dl, 170 mg/dl or more), the
processor calculates an amount of insulin to be delivered to the
host (e.g., an amount of insulin solution sufficient to lower the
host's glucose to or near the predetermined range). In preferred
embodiments, the processor module re-programs the flow profile to
deliver the amount of infusion solution required to deliver the
calculated amount of insulin (e.g., a bolus amount), and the flow
control device infuses the amount of solution responsive to the
re-programming of the flow profile. For example, in some
embodiments, the processor module is configured to insert (e.g.,
add) a medicament infusion phase into the flow profile. As the
host's blood glucose level approaches and/or reaches the
predetermined range, the processor module is configured to
re-program the flow profile to reduce the amount of
insulin-containing solution infused. For example, in some
embodiments, the processor module is configured to re-program the
flow profile to infuse a basal level of insulin, such as during
washing of the sensor.
[0942] Pumpless Sample Withdrawal
[0943] In some circumstances, it is preferred to meter the flow of
a fluid through a vascular access device (including withdrawal of
at blood sample) without the use of a pump and/or a flow control
device (e.g., described above). Accordingly, some embodiments
provide a system for continuously measuring an analyte in an artery
of a host in vivo, which does not require the use of the flow
control device of the preferred embodiments or of a pump.
Accordingly, in some preferred embodiments, the system includes an
arterial infusion system and continuous analyte sensor coupled
thereto. The arterial infusion system is configured and arranged to
meter the flow of a fluid into and/or out of an artery of a host,
and includes an arterial catheter, a pressure transducer, an
infusion fluid, and a pressure system. The pressure system is
configured to increase and/or reduce an amount of pressure applied
to the infusion fluid, such that when the infusion system is
applied to the host (e.g., the catheter is implanted in the host's
artery), the pressure system can infuse the infusion fluid,
withdraw a blood sample, and reinfuse a withdrawn sample into the
host. In general, arteries are pressurized. Accordingly, blood will
expelled from a puncture in the artery (e.g., an inserted/implanted
catheter, a cut or breakage) unless pressure greater than the
arterial pressure is applied thereto, such as via compression, a
pressure cuff, a pressurized infusion system, and the like. An
arterial pressure system can be configured to infuse fluid into the
host by increasing the pressure applied to the infusion fluid, such
as (but not limited to) by increasing the pressure applied with a
blood pressure cuff, such that the applied pressure overcomes the
arterial pressure. In preferred embodiments, the system is
configured to withdraw a sample (e.g., contact the sensor with the
blood sample) by reducing the applied pressure (in a controlled
manner) until a sample of blood is pushed into the catheter (by the
arterial pressure) and contacts the sensor. In some embodiments,
the withdrawn sample is reinfused into the host, such as by
increasing the applied pressure such that the arterial pressure is
again overcome and infusion fluid flows into the host. In some
embodiments, the withdrawn sample is diverted to waste disposal,
such as via a valve. In some embodiments, the system is configured
such that the sensing portion of the sensor are disposed within the
host's body (e.g., within the artery) as described herein. However,
in other embodiments, the sensor is disposed extracorporeally
(e.g., above a plane defined by the host's skin) and the sample is
withdrawn out of the host's body. In preferred embodiments, the
system includes electronics configured to regulate the pressure
system, such that infusion and sample withdrawal are
controlled.
[0944] The analyte sensor can be configured to detect a variety of
analytes, as described elsewhere herein. In some embodiments, the
analyte sensor includes a single working electrode, which generates
a first signal associated with the concentration of the analyte in
the sample. In other embodiments, the analyte sensor is a
dual-electrode continuous analyte sensor, as described elsewhere
herein, and includes a first working electrode configured to
generate the first signal (including an analyte-related signal
component and a non-analyte-related signal component) and a second
working electrode is configured to generate a second signal
(including the non-analyte related signal component).
[0945] In some embodiments, a method for continuously measuring an
analyte in an artery of a host in vivo is provided. In this
embodiment, the method includes the steps of coupling a continuous
analyte sensor with an arterial catheter system applied to a host,
wherein the sensor is configured to generate an analyte-related
signal associated with an analyte in a sample, and wherein the
arterial catheter system includes an arterial catheter, a pressure
transducer, an infusion fluid, and a pressure system configured to
increase and/or reduce an amount of pressure applied to the
infusion fluid; reducing the amount of pressure, such that a sample
of arterial blood contacts the sensor; and generating the
analyte-related signal with the sensor. In some embodiments, the
coupling step includes coupling the sensor to the arterial
catheter, such as by inserting the sensor into a lumen of the
arterial catheter. In some embodiments, the method includes a step
of reinfusing the sample into the host, such as by increasing the
amount of pressure. In some embodiments, the arterial blood
pressure of the host is monitored, using the pressure transducer.
Arterial pressure monitors are known in the art. In preferred
embodiments, the analyte-related signal is processed to provide an
analyte value. In some embodiments, the signal is also
calibrated.
[0946] In some embodiments, the generating step further includes
generating a second signal with the sensor, wherein sensor includes
a first working electrode configured to generate a first signal
including an analyte-related signal component and a
non-analyte-related signal component and the second working
electrode is configured to generate the second signal including the
non-analyte-related signal component. The first and second signals
can be processed, to provide a processed signal substantially
without a signal component due to the non-analyte-related signal
component, and/or to provide a scaling factor. In some embodiments,
the generating step further includes generating a reference signal
associated with a reference analyte in the sample, wherein the
sensor further includes a reference sensor configured to generate
the reference signal.
[0947] Systems and Methods for Processing Sensor Data
[0948] In general, systems and methods for processing sensor data
associated with the preferred embodiments and related sensor
technologies include at least three steps: initialization,
calibration, and measurement. Although some exemplary analyte
sensors, such as glucose sensors, are described in detail herein,
the systems and methods for processing sensor data can be
implemented with a variety of analyte sensors utilizing a variety
of measurement technologies including enzymatic, chemical,
physical, electrochemical, spectrophotometric, polarimetric,
calorimetric, radiometric, and the like. Namely, analyte sensors
using any known method, including invasive, minimally invasive, and
non-invasive sensing techniques, configured to produce a data
signal indicative of an analyte concentration in a host during
exposure of the sensor to a biological sample, can be substituted
for the exemplary analyte sensor described herein.
[0949] In some embodiments, the sensor system is initialized,
wherein initialization includes application of the sensor and/or
sensor system in or on the host. In some embodiments, the sensor
system includes a computer system including programming configured
for performing one or more of the following functions: turning the
system on, requesting and/or receiving initial data (e.g., time,
location, codes, etc), requesting and/or receiving patient data
(e.g., age, conditions, medications, insulin dosing, etc),
requesting and/or receiving calibration information (e.g.,
manufacturer calibration lot data, reference information such as
solution(s) provided for calibration, etc.), requesting information
related to the flow control device, and the like.
[0950] In some embodiments, the sensor system is configured with a
predetermined initial break-in time. In other embodiments, the
sensor system is configured to determine when break-in is complete
(e.g., the sensor signal is substantially stabilized). In some
embodiments, the sensor's sensitivity (e.g., sensor signal strength
with respect to analyte concentration) and/or baseline is used to
determine the stability of the sensor; for example, amplitude
and/or variability of sensor sensitivity and/or baseline may be
evaluated to determine the stability of the sensor signal. In
alternative embodiments, detection of pH levels, oxygen,
hypochlorite, interfering species (e.g., ascorbate, urea, and
acetaminophen), correlation between sensor and reference values
(e.g., R-value), and the like may be used to determine the
stability of the sensor. In some embodiments, sensor stability is
evaluated by determining if and/or when sensor break-in is
complete. In some embodiments, the sensor is configured to
calibrate during sensor break-in, thereby enabling measurement of
the biological sample prior to completion of sensor break-in.
[0951] In one embodiment, systems and methods are configured to
process calibrated sensor data during sensor break-in. In general,
signals associated with a calibration and/or measurement phase of
the sensor system can be measured during initial sensor break-in.
Using a rate method for measuring an analyte (e.g., measuring the
rate of change of a step change), a sensor signal can be calibrated
with a correction factor to account for the rate of change of the
break-in curve. In one exemplary embodiment, the bottom of
sequential step responses (e.g., of calibration phases during
sensor break-in) is fit to a line or curve (e.g., using linear or
non-linear regression, such as least squares regression), to
extrapolate the rate of change of the curve of the sensor break-in.
Accordingly, the rate of change measured in a measurement phase is
corrected to account for the rate of change of the sensor break-in
curve, and the sensor signal calibrated. By calibrating during
sensor break-in, sensor data can more quickly be provided (e.g., to
the user interface) after sensor insertion.
[0952] In some embodiments, systems and methods are configured to
determine an initial baseline value of the sensor. In general,
baseline refers to a component of an analyte sensor signal that is
not substantially related to the analyte concentration. 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/reduction potential that overlaps with hydrogen
peroxide).
[0953] In preferred embodiments, the sensor system includes a
computer system including programming configured to determine
calibration information and calibrate a signal associated with a
biological sample there from. In general, calibration of the signal
includes initial calibration, update calibration and/or
re-calibration of the sensor signal. Although some systems and
methods for calibrating a sensor are described in more detail
elsewhere herein, for example in the section entitled, "Sensor
Electronics," additional and alternative methods for providing
calibration information and calibrating the sensor's signal are
provided in the following description and can be used in
combination with and/or alternative to the methods described
elsewhere herein.
[0954] The term "calibration information" generally refers to any
information, such as data from an internal or external source,
which provides at least a portion of the information necessary to
calibrate a sensor. In some embodiments, calibration information
includes steady state information, such as baseline information
and/or sensitivity information obtained by processing reference
data from an internal and/or external reference source, which is
described in more detail elsewhere herein. In some embodiments,
calibration information includes transient information, such as
rate of change information and/or impulse response information
obtained by processing a signal produced during exposure of the
sensor to a step change (e.g., sudden or nearly sudden change) in
analyte concentration, which is described in more detail elsewhere
herein.
[0955] In some embodiments, steady state information includes
reference data from an external source, such as an analyte sensor
other than the sensor of the sensor system configured to
continuously measure the biological sample, also referred to as
external reference data or external reference value(s). In some
embodiments, calibration information includes one, two, or more
external reference values (e.g., from self-monitoring blood glucose
meters (finger stick meters), YSI Glucose Analyzer, Beckman Glucose
Analyzer, other continuous glucose sensors, and the like). In some
embodiments, one or more external reference values are requested
and/or required upon initial calibration. In some embodiments,
external reference value(s) are requested and/or required for
update calibration and/or re-calibration. In some embodiments,
external reference values are utilized as calibration information
for calibrating the sensor; additional or alternatively, external
reference values can be used to confirm the accuracy of the sensor
system and/or to detect drifts or shifts in the baseline and/or
sensitivity of the sensor.
[0956] In one exemplary embodiment, at least one external reference
value in combination with at least one internal reference value
together provide calibration information useful for calibrating the
sensor; for example, sensitivity of a sensor can be determined from
an external reference value and baseline can be at least partially
determined from an internal reference value (e.g., a data signal
indicative of an analyte concentration in a reference solution
during exposure of the sensor to the reference solution, which is
described in more detail elsewhere herein).
[0957] In another exemplary embodiment, calibration information
includes two or more external reference values that provide
calibration information useful for calibrating the sensor; for
example, at least two SMBG meter values can be used to draw a
calibration line using linear regression, which is described in
more detail elsewhere herein.
[0958] In yet another exemplary embodiment an external reference
value is utilized to confirm calibration information otherwise
determined (e.g., using internal reference values).
[0959] In some embodiments, steady state information includes
reference data obtained from the analyte sensor to be calibrated,
also referred to as internal reference data or internal reference
values. In one exemplary embodiment, internal reference data
includes a signal associated with exposure of the sensor to one or
more reference solutions (e.g., calibration solutions), which is
described in more detail elsewhere herein.
[0960] In some embodiments, the sensor system includes one or more
reference solutions (e.g., calibration solutions in some
embodiments), wherein the system is configured to expose the sensor
to the one or more reference solution(s) to provide calibration
information (e.g., an internal reference value), such as baseline
and/or sensitivity information for the sensor. In one exemplary
embodiment, a reference solution including a known analyte
concentration is provided, wherein the system is configured to
expose the sensor to the reference solution, and wherein the system
is configured to produce a data signal indicative of an analyte
concentration in the reference solution during exposure of the
sensor to the reference solution, as described in more detail
elsewhere herein. In some embodiments, two reference solutions with
two different analyte concentrations are provided. For example, in
order to generate reference values for detecting sensitivity drift
of a glucose sensor, two saline solutions containing 100 and 200
mg/dl glucose respectively can be provided.
[0961] In general the system can be configured to obtain internal
reference values at one or more time points, intermittently, and/or
continuously. For example, in some embodiments, calibration for
drift in baseline and/or sensitivity can be done at set time
intervals, depending upon the severity of the drift. In some
circumstances, it is preferred to calibrate very frequently (e.g.,
between about every 1 minute or less and about every 2, 3, 4, 5,
10, 15, 20 or 30 minutes or longer). In other circumstances, it is
preferred to calibrate less frequently (e.g., about every 1, 2, 3,
5, 10, 15 or 24 hours or longer). For example, in some
circumstances, baseline drift has a substantial effect on sensor
accuracy, while sensitivity drift has little effect. Accordingly, a
baseline calibration solution (e.g., 0-mg/dl glucose) can be used
to calibrate the baseline about every 5 minutes. Thus, to calibrate
for sensitivity drift, an analyte-containing calibration solution
(e.g., 100-mg/dl glucose in saline) can be used to calibrate the
sensor less frequently, such as about once every 1, 2, 3, 5, 10,
12, 24, 48 or more hours. In some embodiments, one or more external
reference values, such as reference values obtained by testing a
blood sample with SMBG or a YSI device, can be used to calibrate
the system, in addition to the internally provided reference values
(e.g., provided via the calibration solutions).
[0962] Although much of the description focuses on the use of a
reference calibration solution to provide an internal reference
value, other sensor technologies, such as optical sensing methods,
are known to provide one or more internal reference standards
(e.g., of known absorbance, reflectance, fluorescence, etc) to
determine baseline and/or sensitivity information, as is
appreciated by one skilled in the art; accordingly, the systems and
methods described herein can be implemented with other types of
internal reference values. Examples of analyte sensors configured
for optical detection of the analyte and/or a reference analyte are
described in detail in the section entitled "Optical Detection,"
above. In some embodiments, a "plateau" is reached when the sensor
has been exposed to the sample of bodily fluid (e.g., blood) or a
reference solution a sufficiently long period of time that the
sensor's enzyme has used up (e.g., reacted with, detected)
substantially all of the available analyte.
[0963] In some embodiments, the sensor system is configured to use
a steady state measurement method, from which steady state
information can be obtained. Steady state information can be
obtained during exposure of the sensor to an analyte concentration
when the signal has reached a "plateau" wherein the signal is
representative of the analyte concentration; the term plateau does
not limit the signal to a flat signal, rather the plateau
represents a time point or time period during which the signal is
substantially stable and a data point that represents the analyte
concentration can be reliably obtained.
[0964] FIG. 11 is a graph that schematically illustrates a signal
produced during exposure of the sensor to a step change in analyte
concentration, in one exemplary embodiment. The x-axis represents
time; the y-axis represents sensor signal (e.g., in counts). In
general, a step change occurs when a sensor is sequentially exposed
to first and second different analyte concentrations, wherein the
signal (after the change from exposure of the sensor to the first
analyte concentration to exposure of the sensor to the second
analyte concentration) includes a measurable rate of change
(transient information) that subsequently "plateaus" or
substantially "plateaus" to a signal that substantially represents
the analyte concentration to which the sensor is exposed (steady
state information). As one example, a step change occurs when a
sensor is exposed to a reference solution of a first analyte
concentration and then subsequently exposed to a reference solution
of a second, different, analyte concentration. As another example,
a step change occurs when a sensor is exposed to a reference
solution of a known analyte concentration and then subsequently
exposed to a biological sample of unknown or uncalibrated analyte
concentration.
[0965] Referring to FIG. 11, at a first time point 1002, a sensor
is exposed to a step change in analyte concentration, for example,
from a zero concentration reference analyte solution to a
biological sample of unknown or uncalibrated analyte concentration.
During the initial signal response to the step change, a rate of
change 1004 of the signal can be measured for a time period. In
some embodiments, for example when the step change is between two
known reference solutions, the rate of change information can
provide transient information useful for calibrating the sensor,
which is described in more detail elsewhere herein. However, if
either of the first and/or second analyte concentrations of the
step response is not known, the rate of change information, alone,
cannot provide sufficient calibration information necessary to
calibrate the sensor.
[0966] Point 1006 represents a point in time that the signal
response shifts from transient information (e.g., rate of change)
to steady state information (e.g., plateau), in some embodiments.
Namely, the signal, beginning at point 1006, substantially
accurately represents the analyte concentration and can be used in
steady state equations to determine an analyte concentration, in
some embodiments. In one exemplary embodiment of steady state
equations useful for calibrating the sensor system, the calibration
information is obtained by solving for the equation y=mx+b,
wherein: "y" represents the sensor data value (e.g., digitized in
"counts") determined at a single point (or averaged value over a
window of data where signal is indicative of analyte concentration,
for example); "b" represents baseline (e.g., unrelated to the
analyte); "m" represents sensitivity (e.g., for a glucose sensor,
counts/mg/dL); and "x" is the concentration of the reference
solution (e.g., known analyte concentration in a reference
calibration solution (e.g., glucose in mg/dL)). In this exemplary
embodiment, steady state information includes sensitivity and
baseline.
[0967] In some embodiments, the sensor data value (y) can be
obtained from a moving window that intelligently selects a plateau
during exposure of the sensor to an analyte concentration. In some
embodiments, the sensor system is configured to be exposed to two
or more known reference calibration solutions from which steady
state information (sensitivity and baseline) can be processed to
calibrate the sensor system; namely, by providing two known analyte
concentrations, the steady state equation described above can be
utilized to solve for baseline and sensitivity of the sensor, which
can be utilized to define a conversion function or calibration
factor, such as described in more detail elsewhere herein.
[0968] Referring again to FIG. 11, point 1006 is a point that can
be used as "y" in the steady state equation described above. In
some embodiments, the point 1006 is easily determinable as it is
the beginning of a signal plateau 1008 (represented by a dashed
line); accordingly, the system includes programming to process the
data signal to determine the signal plateau and/or a time point
therein. In general, a step change produces a signal plateau in the
signal response, which is indicative of a steady state response to
the analyte concentration measurement. In some embodiments, the
system includes programming configured determine the time period
(window) during which the signal has reached a plateau and choose a
single point or average point from that window.
[0969] In some situations, however, the point 1006 and/or plateau
1008 may not be easily determinable. For example, in some sensor
systems, the diffusion of certain non-analyte species (e.g.,
baseline, background and/or interfering species), which may diffuse
more slowly than the analyte (e.g., through a membrane system that
covers the analyte sensor), do not reach a steady state during the
same time period that the analyte reaches a steady state. In these
situations, the signal may not "plateau" in a measurable manner
because of the reaction of the lagging species through the membrane
system, which generate additional signal over the actual analyte
plateau 1008. In other words, while the analyte concentration may
have reached a plateau, the baseline has not. Dashed line 1010
represents the signal response to a step change in such a
situation, for example, wherein the signal does not substantially
"plateau" due to the lagging diffusion of certain non-analyte
species, resulting in a non-measurable analyte plateau. In these
situations, additional information is required in order to provide
calibrated analyte sensor data. Systems and methods for providing
additional information and/or to provide sufficient calibration
information to calibrate an analyte sensor in such situations are
described in more detail below, with reference to conjunctive
measurements, for example.
[0970] In some embodiments, the sensor system is exposed to a
reference solution with a known analyte concentration of about
zero, and wherein the steady state information comprises baseline
information about the sensor in the reference solution. For
example, a glucose sensor system can be exposed to a 0 mg/dl
glucose solution (e.g., an isotonic solution without any glucose
concentration) and the signal associated with the zero glucose
concentration in the reference solution provides calibration
information (steady state) indicative of at least a portion of the
baseline of the sensor.
[0971] It has been observed that, in some circumstances, the signal
associated with the zero glucose concentration in a reference
solution (such as saline) is not equivalent to the baseline signal
when the sensor is exposed to a biological sample (e.g., blood)
from which the sensor is configured to obtain its analyte
concentration measurement; rather the baseline includes an
additional amount of signal associated with the differences between
the composition of the reference solution and the host's blood.
This additional signal is referred to as "offset" (e.g.,
b.sub.offset, see FIG. 11, 1016 and associated text). Offset is an
indication of the level of noise present in the system, the
presence of an interferent in the solution and/or in the blood,
and/or the like. In some circumstances, additional information may
be required in order to determine and/or confirm baseline of a
biological sample (e.g., blood). In some embodiments, 1, 2, 3 or
more external reference analyte values are obtained (e.g., via
finger stick, a clinical analysis device (e.g., YSI) and the like)
and entered into the system, such as for use in determining
b.sub.offset. For example, in some embodiments, the equitation
y=mx+(b+b.sub.offset) is used to calibrate the sensor, wherein m is
determined when the sensor is exposed to calibration solution, b is
determined from the dual-electrode and b.sub.offset is an external
reference value, such as but not limited to a finger-stick
reference value (in counts). In some embodiments, error is
substantially mitigated by evaluating two or more external
reference analyte values for deviation therebetween, such as by
averaging them, detecting outliers, and the like. In one
embodiment, the external reference analyte value is compared to an
estimated or calculated analyte value, such as to confirm the
accuracy of a calculated b.sub.offset. For example, in some
embodiments, the difference between a finger-stick glucose value
(e.g., in counts) and a calculated blood glucose value (e.g., in
counts) is used as the b.sub.offset in future calculations. In some
embodiments, an offset threshold is set, based on a priori
information (e.g., determined from numerous in vitro and/or in vivo
experiments and/or the literature). For example, in some
embodiments, the threshold is based on, at least in part, the
maximum and/or minimum possible offsets for a given sensor
configuration, a give type of host, and/or the like. In some
embodiments, the calibration solution includes additional
components provided to overcome baseline in blood, for example. In
some embodiments, a factor is determined (e.g., from historical
data) to determine an adjustment factor for a difference between
baseline in the biological sample (e.g., blood) and baseline in the
reference solution. In other embodiments, two calibration solutions
are used to evaluate b.sub.offset. In some embodiments, baselines
of the working electrodes is determined prospectively, such as by
testing in the reference solution by the manufacturer. In some
embodiments, the difference in baseline of a biological sample
(e.g., blood) and the baseline of the reference solution, also
referred to as b.sub.offset herein, is determined using other
techniques, such as described in more detail below.
[0972] In general, the calibration information described above,
including a known baseline and sensitivity, can be used to
determine a conversion function or calibration factor applied to
convert sensor data ("y") into blood glucose data ("x"), as
described in more detail elsewhere herein.
[0973] In some embodiments, systems and methods are configured to
obtain transient measurement information associated with exposure
of the sensor to a reference solution of known analyte
concentration and/or a biological fluid of unknown or uncalibrated
analyte concentration. In some embodiments, the system is
configured obtain transient information by exposing the sensor to a
step change in analyte concentration and process the rate of change
of the associated signal. In some embodiments, the system is
configured to obtain transient information by exposing the sensor
to a step change in analyte concentration and processing the
impulse response of the associated signal.
[0974] In one exemplary embodiment, the sensor is exposed to a
first reference solution of a known analyte concentration and then
to a second reference solution of a known analyte concentration to
determine the rate of change of the signal response. In these
embodiments, the equation (.DELTA.y/.DELTA.t=r.DELTA.x) can be used
to obtain the transient information, wherein "Ax" is the difference
between the two known solutions that are being measured (e.g., 0
mg/dL to 100 mg/dL in an exemplary glucose sensor), ".DELTA.y" is
the measured difference between the sensor data (e.g., in counts)
corresponding to the analyte concentration difference in known
reference solutions (.DELTA.x), "At" is the time between the two
"y" sensor measurements referenced with .DELTA.y, and "r"
represents the rate of change calibration factor, or rate of change
conversion function, that can be applied for that particular sensor
to obtain calibrated blood glucose measurements from sensor rate of
change data.
[0975] In some embodiments, transient information can be obtained
from the rate of change of a signal produced during exposure of the
sensor to a biological sample of unknown or uncalibrated analyte
concentration. In some embodiments, transient information can be
obtained from the step and/or impulse response of a signal produced
during exposure of the sensor to a step change in analyte
concentration.
[0976] In some embodiments, neither steady state information, nor
transient calibration measurements are used in isolation in
calibrating the sensor system, but rather steady state and
transient information are combined to provide calibration
information sufficient to calibrate sensor data such as described
in more detail, below. For example, in some embodiments, wherein
baseline is not completely known (e.g., b.sub.offset must be
determined), wherein a rate of change calibration factor is not
easily determinable (e.g., when multiple known reference solutions
cannot be pushed substantially immediately adjacent to each other
to provide a rate of change indicative of the step or impulse
response), wherein the a steady state measurement cannot be
obtained (e.g., due to lagging species affecting the analyte signal
plateau), and the like. In some embodiments, both steady state
information and transient information are processed by the system
to provide sensor calibration, confirmation, and/or diagnostics. In
some embodiments, transient sensor information from unknown or
uncalibrated blood glucose measurements can be processed to provide
calibration information for the sensor system, such as described in
more detail below.
[0977] In some embodiments, once at least a portion of the
calibration information is determined, the sensor system is
configured to expose the sensor to a biological sample and measure
a signal response thereto. In some embodiments, the sensor can be
continuously exposed to the biological sample, wherein at least
some external reference values are used as calibration information
for calibrating the sensor system. In some embodiments, the sensor
can be intermittently exposed to the biological sample, wherein at
least some internal reference values are used as calibration
information for calibrating the sensor system, also referred to as
auto-calibration in some exemplary embodiments.
[0978] In some embodiments, the sensor system is calibrated solely
using steady state information, such as described in more detail
elsewhere herein. In one such embodiment, the sensor system is
configured to be exposed to a biological sample and a value (y)
determined from the signal plateau, which is used in combination
with a conversion function (calibration factor) that uses steady
state information (e.g., sensitivity and baseline) to obtain a
calibrated analyte concentration (e.g., glucose concentration in
mg/dL or mmol/L) equivalent to the measured sensor data value
y.
[0979] In general, the sensor system of the preferred embodiments
can be configured to utilize any combination the steady state
information (e.g., from external and/or internal sources) described
in more detail elsewhere herein. In some embodiments, the sensor
system includes systems and methods configured to calibrate the
sensor based on one, two, or more external reference values. In
some embodiments, the sensor system includes systems and methods
configured to calibrate the sensor based on one or more external
reference values, which calibration can be confirmed using an
internal reference value (e.g., zero analyte concentration
reference solution). In some embodiments, the sensor system
includes systems and methods configured to calibrate the sensor
based on one external reference value in combination with one
internal reference value to determine baseline and sensitivity
information. In some embodiments, the sensor system includes
systems and methods configured to calibrate the sensor based on
internal reference values, also referred to as auto-calibration. In
general, auto-calibration includes the use of one or more reference
solution to calibrate the sensor system. In some embodiments, the
sensor system includes systems and methods configured to calibrate
the sensor based on prior information, which is described in more
detail elsewhere herein. In some embodiments, the sensor system
includes systems and methods configured to calibrate the sensor
based on dual working electrodes, by substantially eliminating the
baseline component of the steady state calibration equation (e.g.,
(y=mx)).
[0980] In some embodiments, the sensor system includes systems and
methods configured to calibrate the sensor based solely on
transient information (e.g., rate of change, decay, impulse
response, etc) described in more detail elsewhere herein. In one
exemplary embodiment, analyte concentration can be determined from
the change in sensor data responsive to a step change (.DELTA.x),
the time (.DELTA.t) elapsed between the sensor data measurements
.DELTA.y, and the rate of change calibration factor/rate of change
conversion function, such as described in more detail above.
[0981] In some embodiments, the sensor system includes systems and
methods configured to calibrate the sensor based on conjunctive
information, wherein the calibration information used to calibrate
the sensor system includes both steady state information and
transient information.
[0982] In one exemplary embodiment, the sensor system includes
systems and methods configured to calibrate the sensor based on a
rate of change (transient information) associated with a signal
produced during exposure of the sensor to a step change between a
reference solution of known analyte concentration (e.g., 0 mg/dl
glucose) and a biological sample; in this exemplary embodiment, a
reference value (steady state information) from an external analyte
sensor (e.g., blood glucose meter) can be obtained for the analyte
concentration in the biological sample, thereby providing
sufficient information to solve for calibration using rate of
change of the signal response to the step change there between. One
advantage of using rate of change calibration methods includes its
insensitivity to baseline and interfering species.
[0983] In one preferred embodiment, a system is provided for
monitoring analyte concentration in a biological sample of a host,
the system including: a substantially continuous analyte sensor
configured to produce a data signal indicative of an analyte
concentration in a host during exposure of the sensor to a
biological sample; a reference solution including a known analyte
concentration, wherein the system is configured to expose the
sensor to the reference solution, and wherein the sensor is
configured to produce a data signal indicative of an analyte
concentration in the reference solution during exposure of the
sensor to the reference solution; and a computer system including
programming configured to determine calibration information and
calibrate a signal associated with a biological sample there from,
wherein the calibration information includes steady state
information and transient information. In some embodiments, the
calibration information is determined from a signal associated with
exposure of the sensor to the reference solution and a signal
associated with exposure of the sensor to a biological sample.
[0984] One situation wherein steady state information and transient
information are useful together for calibrating a sensor system
includes a situation where a baseline measurement obtained from an
internal reference (b.sub.reference) provides only a portion of the
baseline information necessary for calibrating the sensor system.
As one example, the baseline of blood is different from the
baseline of saline (e.g., reference) and compounds or molecules
that make up the baseline in blood can create artifacts (e.g.,
b.sub.offset), which can make calibration using internally derived
steady state information alone, difficult. Namely, plateau 1008
(FIG. 11) in the signal responsive to the step change in analyte
concentration does not occur in blood, in some embodiments, due to
slow diffusion of baseline-causing compounds/molecules to the
sensor electroactive surface; instead, an artifact 1010 (FIG. 11)
is observed in the signal. Accordingly, in some embodiments,
baseline information useful for calibration of a sensor system
includes both b.sub.reference and b.sub.offset. A variety of
systems and methods of determining b.sub.offset, which can be
useful in providing calibration information and/or diagnostics and
fail-safes, has been discovered, as described in more detail
elsewhere herein.
[0985] In some embodiments, b.sub.offset can be determined from
transient information derived from a signal associated with
exposure of the sensor to a biological sample, wherein the
biological sample is of unknown or uncalibrated analyte
concentration.
[0986] In one preferred embodiment, a system for monitoring analyte
concentration in a biological sample of a host is provided, the
system including: a substantially continuous analyte sensor
configured to produce a data signal indicative of an analyte
concentration in a host during exposure of the sensor to a
biological sample; a reference solution including a known analyte
concentration, wherein the system is configured to expose the
sensor to the reference solution, and wherein the system is
configured to produce a data signal indicative of an analyte
concentration in the reference solution during exposure of the
sensor to the reference solution; and a computer system including
programming configured to determine calibration information and
calibrate a signal associated with a biological sample there from,
wherein the calibration information is determined from a signal
associated with exposure of the sensor to the reference solution
and a signal associated with exposure of the sensor to a biological
sample, wherein the biological sample is of unknown or uncalibrated
analyte concentration.
[0987] In some embodiments, systems and methods are configured to
process an impulse response of a signal associated with exposure of
the sensor to a biological sample, wherein the biological sample is
of unknown or uncalibrated analyte concentration, in order to
determine an offset between a baseline measurement associated with
a reference solution and a baseline measurement associated with a
biological sample (e.g., b.sub.offset).
[0988] FIG. 12 is a graph that schematically illustrates a
derivative of the step response shown in FIG. 11. FIG. 12 can also
be described, as the impulse response of the signal associated when
a sensor is exposed to a step change to a biological sample of
unknown or uncalibrated analyte concentration, in one exemplary
embodiment. In this embodiment, the impulse response can be defined
by a sum of two exponentials functions (e.g.,
(ae.sup.-k1*t-ae.sup.-k2*t), where k1 and k2 are time constants
characteristic of the sensor), wherein the impulse response starts
at 0 at t=0 and is expected to decay to 0 as t becomes large (as
time passes). The impulse response reaches a peak, shown as point
1050 in FIG. 12, which represents the maximum rate of change of the
associated signal (see FIG. 11, for example). Additionally,
although it is expected that the signal will decay to 0 as t
becomes large, FIG. 12 illustrates a plateau 1052 above the y-axis;
namely, wherein the plateau 1052 does not hit 0.
[0989] It has been discovered that the positive value 1054 of the
plateau substantially represents the slope of the b.sub.offset
artifact 1010 (FIG. 11). Accordingly, when the slope is drawn from
t=0 of the step response (see line 1012 of FIG. 11), the "y" value
1016 of that slope line at the end of the step response 1014,
represents b.sub.offset. Accordingly, b.sub.offset can then be
added to the equation y=mx+b (where b=b.sub.reference b.sub.offset)
and a conversion function (calibration factor) can be determined to
calibrate the sensor system (i.e., using both steady state
information and transient information and including using the
signal associated with exposure of the sensor to a biological
sample of unknown or uncalibrated analyte concentration.)
[0990] In some alternative embodiments, systems and methods are
configured to process an impulse response (such as shown in FIG.
12) associated with a step change (such as shown in FIG. 11) to
determine a time point of a steady state measurement during which
an analyte concentration can be obtained. As described above, in
some circumstances, it can be difficult to determine a steady state
time point (e.g., 1006 in FIG. 11) at which time point the signal
accurately represents the analyte concentration. Accordingly,
systems and methods configured to determine the time point (e.g.,
1006 in FIG. 11) in the step response associated with exposure of
the sensor to a biological sample of unknown or uncalibrated
analyte concentration have been discovered, which time point
accurately represents the analyte concentration in the biological
sample. Because the impulse response can by defined by exponentials
(discussed above), systems and methods can be configured to process
the exponential equation(s) with variable parameters to determine a
best-fit to the impulse response curve determined from exposure of
the sensor to the biological sample. It has been discovered that
this best fit of the impulse response provides sufficient
information to determine the time point 1056 (FIG. 10) at which the
decay curve should have decayed to the y-intercept; namely, the
time point 1056 where the decay curve should have hit y=0 indicates
the (steady state) time point in the step response (e.g., 1006 in
FIG. 11) that accurately represents the analyte concentration
without the b.sub.offset artifact 1010. Accordingly, (y=mx+b) can
then be used to calibrate the sensor system, including the signal
value "y" at the time indicated by the extrapolated impulse
response curve (e.g., and using sensitivity and baseline
information determined from one or more reference calibration
solutions, such as described in more detail elsewhere herein.
[0991] In some other alternative embodiments, systems and methods
are configured to compare steady state information and transient
information for a plurality of time-spaced signals associated with
biological samples of unknown or uncalibrated analyte concentration
to determine an offset between a baseline measurement associated
with a reference solution and a baseline measurement associated
with the biological samples.
[0992] In some exemplary embodiments, b.sub.offset is determined by
plotting level (i.e., the point at which the step response plateaus
or ends) vs. rate (i.e., maximum rate of change of the step
response determined from the peak of the impulse response curve)
for a plurality of step responses (e.g., time-spaced signals) and
drawing a regression line of the plotted points, such as described
in more detail with reference to FIG. 13.
[0993] FIG. 13 is a graph that illustrates level vs. rate for a
plurality of time-spaced signals associated with exposure of the
sensor to biological samples of unknown or uncalibrated analyte
concentration. The y-axis represents maximum rate of change for
each step response; the x-axis represents level (signal level
(e.g., in counts) obtained at the plateau of the signal and/or the
end of the step response.) Each point 1080 on the plot represents
level vs. rate for each of the plurality of time-spaced signals. A
regression line 1082 is drawn using known regression methods, as is
appreciated by one skilled in the art. The point 1084 at which the
line 1082 crosses the y-axis represents the signal associated with
a reference (e.g., 100 mg/dL calibration solution) plus
b.sub.offset. Accordingly, b.sub.offset can be determined by
subtracting the signal associated with the reference from the point
1084 at which the line 1082 crosses the y-axis. Thus, b.sub.offset
determined from the plot as described above, can be included in the
equation y=mx+b (where b=b.sub.reference+b.sub.offset) and a
conversion function (calibration factor) can be determined to
calibrate the sensor system (i.e., using both steady state
information and transient information and including using the
signal associated with exposure of the sensor to a biological
sample of unknown or uncalibrated analyte concentration.)
[0994] In some embodiments, b.sub.offset is an adjustable
parameter, wherein the sensor system includes systems and methods
configured to determine b.sub.offset with each measurement cycle
(each time the sensor is exposed to the biological sample) and to
adjust the calibration factor (conversion function), including
b.sub.offset with each measurement cycle, responsive to a change in
b.sub.offset above a predetermined threshold, and/or responsive to
external information, for example.
[0995] In some embodiments, systems and methods are provided to
detect a shift in the baseline and/or sensitivity of the signal
based on a comparison of steady state information and transient
information, such as described in more detail with reference to
FIG. 13. In some embodiments, systems and methods are provided to
correct for a shift in the baseline and/or sensitivity of the
signal based on a comparison of steady state information and
transient information. In some embodiments, systems and methods are
provided to initiate a calibration responsive to detection of a
shift in the baseline and/or sensitivity of the signal based on a
comparison of steady state information and transient
information.
[0996] Referring again to FIG. 13, regression line 1082 is shown
for a selected plurality of time spaced signals. In some
embodiments, multiple regression lines can be drawn for a plurality
of different windows of time spaced signals (e.g., time-shifted
windows). In these embodiments, a comparison of a regression line
from a first window of time spaced signals as compared to a
regression line drawn from a second window of time spaced signals
can be used to diagnose a shift and/or drift in sensor sensitivity
and/or baseline. For example, in FIG. 13, line 1082 represents a
regression line drawn for a first window of data over a first
period of time; dashed line 1086 represents a regression line drawn
for a second window of data over a second period of time; and
dashed line 1088 represents a regression line drawn for a third
window of data over a third period of time. In this example, dashed
line 1086 is shifted along the y-axis from the first line 1082,
indicating a drift or shift in the sensor's baseline from the first
time period to the second time period; dashed line 1088 is shifted
along the x-axis from the first line 1082, indicating a drift or
shift in the sensor's sensitivity from the first time period to the
third time period. Accordingly, a shift in the regression line can
be used to diagnose a shift or drift in the sensor's signal and can
be used to trigger a corrective action, such as update calibration
and/or re-calibration using any of the methods described herein.
Additionally or alternatively, the shift in the line can be used to
correct a shift or drift in the sensor's signal; for example, the
amount of shift in the line can be used to update calibration
accordingly (e.g., the change in y-value between two regression
lines can be representative of a corresponding change in baseline
between two time periods, and the calibration information updated
accordingly). One skilled in the art appreciates that some
combination of shift or drift of the baseline and sensitivity can
occur in some situations, which can be similarly detected and/or
corrected for.
[0997] Sensor Sensitivity Evaluation
[0998] In some circumstances, noise on the sensor signal can be
mistaken as a drift in sensor sensitivity. It has been empirically
determined, through evaluation of large in vivo and/or in vitro
data sets, that sensor sensitivity generally follows an expected
pattern of drift, over the period of sensor use. For example, in
one exemplary sensor configuration, during the first hour or so, of
sensor use (e.g., after start-up and/or re-start-up after a period
of disuse), sensitivity tends to change rapidly; after this period,
the sensitivity increase tends to level off and/or plateau. However
other sensitivity profiles are possible based on sensor design.
While each individual sensor's sensitivity profile can vary from
that of other such sensors, depending upon factors such as sensor
design, membrane chemistry, implantation site, and the like, it has
been found that sensor profiles tend to follow an empirically
determined pattern of drift within a range of about .+-.5%,
.+-.10%, .+-.15%, .+-.20% or .+-.25%. Deviations from the expected
pattern can be indicative of noise on the sensor, sensor failure,
and/or the like, which can be dealt with as described elsewhere
herein, such as the section entitled "Diagnostics and
Fail-Safes."
[0999] FIG. 14 is a flow chart illustrating sensor sensitivity
evaluation, in some embodiments. In preferred embodiments, systems
and methods are configured to process a plurality of sensitivity
calculations, to determine if an apparent sensitivity drift falls
within the expected profile.
[1000] At block 1400, a method for evaluating a change in
sensitivity of an analyte sensor over a predetermined time period
is provided. In some embodiments, the predetermined time period is
relatively short, such as but not limited to less than or equal to
about 30 minutes, also referred to as short-term sensitivity
evaluation. In some embodiments, relatively shorter periods of
time, such as 25, 20, 15, 10, 5 minutes are preferred. For example,
in one embodiment, the evaluated sensitivities are calculated about
every 5 minutes. In other embodiments, the predetermined time
period is longer. For example, in one embodiment, the time period
is at least about 30 minutes, also referred to as long-term
sensitivity evaluation. In other embodiments, the predetermined
time period is at least about 60 minutes. For example, in some
embodiments, the predetermined time period is about 70, 80, 90,
100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 minutes, or
longer.
[1001] At block 1402, sensor data is received from an analyte
sensor. For example, in some embodiments, the system includes an
input module, also referred to as the processor module, configured
to receive the sensor analyte data. The sensor data can include one
or more sensor analyte values measured in a bodily fluid of a host
(e.g., blood). In some embodiments, an individual measurement is
used. In some embodiments, an average of a plurality of time-spaced
points is used. In some embodiments, reference analyte values are
also received by the input module. For example, in vivo reference
analyte values can be generated when the sensor is contacted with a
reference solution. In some embodiments, reference analyte values
are intermittently received. For example, in some embodiments, the
in vivo reference analyte values are generated when the sensor is
intermittently in contact with the reference solution (e.g.,
calibrant), such as according to the flow profile (e.g., see FIG.
10E). For example, if the sensor is included in an integrated
system, such as depicted in FIG. 6 and as described with reference
to FIGS. 10A-10E, wherein the flow control device moves between the
controlled flow and gravity flow valve positions, such as at flow
rates and times specified by the flow profile, and the sensor
generates sensor data when the sensor is contacted with blood and
reference values when the sensor is in contact with the reference
solution. Additionally or alternatively, in some embodiments, the
reference analyte value(s) are obtained from an in vitro analyte
monitor (e.g., external reference analyte values). For example, a
self monitored blood glucose monitor can be used to obtain external
reference glucose values (e.g., from a finger-stick blood sample),
which can be entered into the system, as described elsewhere
herein.
[1002] At block 1404, analyte sensor sensitivity is calculated
intermittently (e.g., periodically or non-periodically), based at
least in part on the reference analyte data, such as described
elsewhere herein. For example, in some embodiments, the processor
module is configured to and/or includes programming that calculates
sensor sensitivity using the formula y=mx+b, wherein m is the
sensitivity value (e.g., estimated and/or measured). For example,
in some embodiments, the intermittently received reference analyte
values are used to intermittently calculate the sensitivity of the
analyte sensor, such as but not limited to from about once every
0.25, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20, 25 or 30-minutes to about once every 1, 1.5, 2, 2.5
or 3-hours or longer. In some embodiments, a plurality of
sensitivities is calculated over a predetermined time period. For
example, in some embodiments, the processor is configured to and/or
includes programming that calculates 2, 3, 4, 5, 6, 7, 8, 9, 10 or
more sensitivities over a pre-programmed time period of 10, 15, 20,
30, 40, 50, 60, 70, 80, 90 or 120-minutes or longer. In some
embodiments, the sensitivities are calculated iteratively. For
example, as the integrated system cycles through phases of blood
and reference solution measurement according to the system's (e.g.,
the processor module's) flow profile (e.g., programming). In some
embodiments, the sensitivity values are filtered, such that each
calculated sensitivity value is a filtered value. For example, in
some embodiments, the data (e.g., reference analyte values) are
filtered prior to use in calculation of the sensor sensitivity m
(e.g., via an IIR or FIR filter). In another example, in some
embodiments, the data (within a window of data) are averaged (e.g.,
equally or non-equally weighted average, mean-value, median, or the
like) prior to use in calculation of sensor sensitivity. In yet
another example, in some embodiments, two or more calculated
sensitivities are filtered, averaged, smoothed, and/or the
like.
[1003] At block 1406, a plurality of time-spaced sensitivity
calculations are evaluated over a predetermined time period. For
example, in some embodiments, the plurality of time-spaced sensor
calculations are evaluated to determine whether or not the sensor's
sensitivity did change (e.g., drift), and if so, did the change in
calculated sensitivities follow the empirically determined pattern,
was the observed change due to noise, and the like, as described
below. In some embodiments, the processor is configured to
calculate a change (e.g., drift) in sensor sensitivity using the
formula
Drift = m t 1 - m t 2 m t 1 ##EQU00004##
and/or the formula
Drift = m t 1 - m t 2 ( m t 1 + m t 2 ) / 2 , ##EQU00005##
wherein m.sub.t1 is the calculated sensitivity at time 1, and
m.sub.t2 is the calculated sensitivity at time 2, for example. In
preferred embodiments, this evaluation is performed iteratively on
the plurality of time-spaced sensitivity calculations over the
predetermined time period. In some embodiments, at least two
sensitivity values are evaluated during the predetermined time
period. For example, in some embodiments, the difference between
two sensitivity calculations (e.g., the amount of change) is
evaluated. In some embodiments, the at least two sensitivity values
are averaged and/or filtered (e.g., smoothed to remove noise)
before they are evaluated. Filtering the sensitivity calculations
can provide a smoother trajectory (e.g., curve) for evaluation of
sensitivity drift by eliminating outliers and/or random noise
(e.g., non-specific noise). The sensitivity calculations can be
filtered using a variety of methods (e.g., FIR, IIR, averaging) as
described elsewhere herein. In other embodiments, all of the
sensitivity calculations over the time period are evaluated. In
further embodiments, all sensitivity calculations are evaluated at
a plurality of time points during sensor use. For example, a sensor
session can last from the time when the sensor is implanted and/or
the flow control device is turned on to the time when the system is
turned off and/or the sensor is removed. In another example, a
sensor can be implanted for an extended period of time, such as
three or more days, with intermittent periods of use (e.g., when
the power is on and the system is functioning). For example, the
system may be intermittently powered down, such as during certain
medical procedures. The period of sensor use before the powering
down is considered to be a sensor session, in some embodiments.
Similarly, the period of sensor use after the restart (e.g.,
power-up, re-power-up) is considered to be a sensor session, in
some embodiments.
[1004] In some embodiments, a change in sensitivity is evaluated by
comparing it (the change in sensitivity) with one or more criteria.
For example, in some embodiments, a priori sensitivity information
is used (at least in part) to evaluate the change in sensitivity.
In general, a priori information includes information, data and/or
observations generated during many previous in vitro and/or in vivo
experiments, as well as information, data, and/or observations
gleaned from the scientific literature. In some embodiments, the a
priori sensitivity information includes and/or provides an expected
profile (e.g., an expected pattern and/or amount of sensitivity
change/drift over time). For example, it has been observed that in
some sensor designs, the sensor sensitivity tends to increase over
time, wherein the increase tends to occur within an expected range.
For example, it has been observed that sensor sensitivity tends to
increase over time (e.g., no substantial decrease over time),
wherein the increase tends to occur within an expected range,
wherein the magnitude of the change is related to the length of
time the sensor has been used and/or implanted and/or energized
(e.g., turned on). Deviation from the expected profile can be
indicative of a failure of a portion of the integrated system, a
detrimental change in the host's condition, and/or the like, in
some embodiments. In some embodiments, the system is configured to
evaluate and/or consider a deviation from the expected profile in
combination with additional information (e.g., interferents, noise,
completion of break-in, etc.) to determine if a system failure has
occurred.
[1005] In some embodiments, the a priori sensitivity information
defines a range (e.g., within boundaries and/or guard bands) of
acceptable change (increase and/or decrease) in sensitivity. For
example, in some circumstances, sensitivity can change (e.g.,
drift) up to about .+-.5%, .+-.10%, .+-.15%, .+-.20%, .+-.25%,
.+-.30%, .+-.40%, .+-.50%, .+-.60%, .+-.70%, .+-.80%, .+-.90%,
.+-.100%, .+-.200% or more over a given time period (e.g., over a
time period of about 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90,
100, 110 or 120 minutes or longer). In some embodiments, an
acceptable change in sensitivity is related to how long the sensor
has been in use, implanted and/or energized.
[1006] In some embodiments, a change in sensitivity is evaluated
using a "cone" of feasible sensitivity values of the sensor, such
that aberrant sensitivity changes (e.g., artifacts) are detected
whenever the sensitivity value (e.g., amount of sensitivity change,
a calculated change in sensitivity over a time period) falls (e.g.,
occurs) outside of the cone of possibility. In one embodiment, the
cone of possible sensitivity values is defined in terms of a range
of allowable (or feasible) sensitivity change for a time point
during a sensor session. The range of allowable sensitivity change
can change over time during a sensor session, for example, by
allowing a greater sensitivity change during an earlier time period
of a sensor session than a later time period of a sensor session.
In general, sensitivity information depends upon sensor design and
can be obtained from analysis of data sets (e.g., a priori
information). A known feasible range can be represented (e.g.,
drawn) on a graph as a "cone of possible sensitivity values" (e.g.,
a range of possible calculated sensitivity values, for the next
time period, based at least in part on one or more previously
calculated sensitivity value(s) and a priori information). In some
embodiments, one or more criteria used to determine the cone of
possible sensitivity values are defined by an expected profile. For
example, the cone of possibility initiates at the calculated
sensitivity value of a first time period (e.g., the point of the
cone) and projects forward in time (e.g., becomes broader), such
that the broadest portion of the cone (e.g., the "base" of the
cone) is located at and/or is projected toward or past the second
time period. At the second calculated sensitivity value graphed,
another "cone of possibility" can be drawn for the next time period
(e.g., a third time period), wherein this new cone of possibility
is based on the expected profile, and so on.
[1007] Accordingly, in embodiments wherein sensitivity is evaluated
in the short-term (e.g., over periods of 30-minutes or less), when
the change in sensitivity meets the one or more criteria (e.g.,
falls within the boundaries of the expected profile, is within a
cone of feasible change, and/or the like), the system is configured
to use the most recent sensitivity calculation evaluated (e.g., for
sensor calibration and the like). Similarly, the system is
configured to not use a most recent sensitivity calculation
evaluated to calibrate the analyte sensor when the change in
sensitivity does not meet one or more criteria. In some
circumstances, the change in sensitivity not meeting the one or
more criteria can trigger a sensor failure, an alert, an alarm, a
fail-safe, and the like, as described elsewhere herein.
[1008] In some embodiments, evaluation of sensor sensitivity is
conducted using a dual-electrode continuous analyte sensor. As
described elsewhere herein, a dual-electrode analyte sensor
includes two working electrodes, which are configured to provide
two signals. The first signal includes an analyte component and a
baseline component. The second signal includes a baseline component
without an analyte component. As described elsewhere herein, in
some embodiments, sensitivity of a dual-electrode analyte sensor is
calculated using the signal from either (or both) of the working
electrodes. Accordingly, in some embodiments, the intermittent
sensor sensitivity calculations are based at least in part on the
first signal or based at least in part on the second signal. In a
further embodiment, the second signal is subtracted from the first
signal to obtain a subtracted signal, wherein the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on a subtracted signal, combined with
signals measured by the sensor when exposed to reference solution
and/or blood. In some embodiments, a difference in sensitivities of
the plus-enzyme and no-enzyme working electrodes is evaluated. For
example, with respect to a dual-electrode glucose sensor exposed to
a calibration solution (e.g., a glucose-containing infusion
solution) the sensitivity measured by the no-enzyme electrode can
be used as the sensitivity value for the enzyme electrode and/or
subtracted signal as described in more detail elsewhere herein.
[1009] In some embodiments, sensor sensitivity can be calculated
using an external reference value generated from a blood sample
(e.g., a split sample, finger-stick), wherein the external
reference value is measured using another test device, at the
bedside or in a clinical laboratory. For example, in the case of
glucose sensors, external reference values can be generated by a
finger-stick or testing a blood sample using an YSI device. Use of
external reference values (e.g., baseline value obtained via
finger-stick and/or YSI) in calculation of sensor sensitivity is
preferred in some embodiments, such as but not limited to
non-dual-electrode continuous analyte sensors.
[1010] In an exemplary embodiment, a method for evaluating a change
in sensitivity of an analyte sensor over a predetermined time
period is provided, wherein sensor data is received from an analyte
sensor, wherein the sensor data includes one or more sensor analyte
values measured in a biological sample of a host, a sensitivity of
the analyte sensor is intermittently calculated based at least in
part on reference analyte data, and a change in sensitivity is
evaluated by evaluating a plurality of time-spaced sensitivity
calculations over a predetermined time period. For example, the
processor module is configured to and/or includes programming that
evaluates the change in sensitivity of the analyte sensor over the
predetermined time period. In some embodiments, the predetermined
time period is less than or equal to about 30, 25, 20, 15, 10, or 5
minutes. In other embodiments, the predetermined time period is at
least about 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120
minutes.
[1011] In another exemplary embodiment, a system for evaluating a
change in sensitivity of an analyte sensor over a predetermined
time period is provided. In this embodiment, the system includes a
computer system including an input module configured to receive
sensor analyte data and reference analyte data, wherein the sensor
data includes one or more sensor analyte values measured in a
biological sample of a host and wherein the reference data includes
one or more reference analyte values, and a processor module
configured to (1) intermittently calculate a sensitivity of the
analyte sensor based at least in part on the reference analyte data
and to (2) evaluate a change in sensitivity by evaluating a
plurality of time-spaced sensitivity calculations over a
predetermined time period. In some embodiments, the predetermined
time period is less than or equal to about 30, 25, 20, 15, 10, or 5
minutes. In other embodiments, the predetermined time period is at
least about 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120
minutes.
[1012] In some embodiments, wherein the predetermined time period
is less than or equal to about 30 minutes, also referred to as
short term sensitivity evaluation, evaluating a change in
sensitivity includes evaluating at least two sensitivity
measurements during the predetermined time period. For example, the
processor module is configured to and/or includes programming that
evaluates at least two sensitivity measurements during the
predetermined time period, to evaluate the change in sensitivity.
For example, in one embodiment, the at least two sensitivity
measurements are separated by 30 minutes. In other embodiments, the
at least two sensitivity measurements are separated by 25, 20, 15,
10, or 5 minutes. In some further embodiments, the processor module
is configured to and/or includes programming that averages and/or
filters the at least two sensitivity measurements prior to
evaluating the at least two sensitivity measurements. In some
circumstances, averaging and/or filtering the at least two
sensitivity measurements can reduce the affect of outlier data
points on the evaluation.
[1013] In some embodiments, wherein the predetermined time period
is less than or equal to about 30 minutes, the processor module is
configured to and/or includes programming that compares the change
in sensitivity with one or more criteria. For example, the one or
more criteria include but are not limited to an expected profile of
sensitivity change for the time period and/or a cone of possibility
(e.g., a range of allowable sensitivity change), such as described
above. In some embodiments, the processor module is configured to
and/or includes programming that uses a most recent sensitivity
calculation evaluated to calibrate the analyte sensor when the
change in sensitivity meets one or more criteria. In other
embodiments, the processor module is configured to and/or includes
programming that does not use a most recent sensitivity calculation
evaluated to calibrate the analyte sensor when the change in
sensitivity does not meet one or more criteria.
[1014] In some embodiments, wherein the predetermined time period
is less than or equal to about 30 minutes, the step of
intermittently calculating a sensitivity of the analyte sensor
includes intermittently receiving a reference analyte value. For
example, in some embodiments, the processor module (also referred
to as a receiving module) is configured to and/or includes
programming that intermittently receives the reference analyte
value(s). In some circumstances, reference analyte values can be
measured by the system. In some embodiments, the system is
configured to periodically receive a measured analyte concentration
from a reference analyte solution. For example, in some
embodiments, the sensor is exposed to the reference analyte
solution, such that the sensor measures the analyte concentration
of the reference analyte solution. In other embodiments, the
reference analyte values are measured outside of the system. For
example, in some embodiments, a reference analyte value obtained
from an in vitro analyte monitor is received by the system.
[1015] In some embodiments, wherein the predetermined time period
is less than or equal to about 30 minutes, the step of evaluating a
sensitivity is iteratively performed on the plurality of
time-spaced sensitivity calculations over the predetermined time
period. For example, in some embodiments, the processor module is
configured to and/or includes programming that evaluates a
sensitivity calculation every 5, 10, 15, 20, 25 or 30 minutes.
[1016] In some embodiments, wherein the predetermined time period
is at least about 30 minutes, also referred to as long term
sensitivity evaluation, the processor module is configured to
and/or includes programming that iteratively performs the
sensitivity evaluation on the plurality of time-spaced sensitivity
calculations over the predetermined time period (e.g., at least
about 30 minutes). In some embodiments, the step of evaluating a
sensitivity includes evaluating all of the sensitivity calculations
over a sensor session. For example, if the sensor session is
3-days, then all of the sensitivity calculations from the sensor
session up to the time of sensitivity evaluation are evaluated.
Similarly, if the sensor session lasts 4, 5, 6, or 7 days, then all
of the sensitivity calculations over that period of days are
evaluated. In some embodiments, the processor module is configured
to evaluate a sensitivity based at least in part on a priori
sensitivity information. For example, a priori sensitivity
information can be obtained from previous sensor uses, such as
numerous in vitro and/or in vivo experiments. In some embodiments,
the a priori sensitivity information includes an expected profile.
For example, during the first hour of sensor use, the expected
profile may be a line having a slope and/or curvature within a
first range; while during the second hour of use the expected
profile may be a line having a slope and/or curvature within a
second range. In some embodiments, the a priori sensitivity
information defines a range of acceptable change in sensitivity,
such as described with reference to a cone of possible acceptable
and/or feasible sensitivity changes. For example, a range of
acceptable change in sensitivity can include changes in sensitivity
observed 80%, 85%, 90% or 95% of the time, in numerous previously
conducted in vitro and/or in vivo experiments (e.g., uses), for a
given time period of sensor use and/or implantation.
[1017] In some embodiments of evaluating a change in sensitivity of
an analyte sensor over a predetermined time period, the analyte
sensor includes two working electrodes configured to provide a
first signal (e.g., from the plus-enzyme working electrode)
including an analyte component and a baseline component and a
second signal e.g., from the no-enzyme (e.g., non-enzymatic)
working electrode) including a baseline component without an
analyte component. In some further embodiments, the processor
module is configured to and/or includes programming that
intermittently calculates a sensitivity of the analyte sensor based
at least in part on the first signal. In some further embodiments,
the step of intermittently calculating a sensitivity of the analyte
sensor is based at least in part on the second signal. In some
further embodiments, the processor module is configured to and/or
includes programming that subtracts the second signal from the
first signal to obtain a subtracted signal, wherein the step of
intermittently calculating a sensitivity of the analyte sensor is
based at least in part on the subtracted signal.
[1018] In some embodiments of evaluating a change in sensitivity of
an analyte sensor over a predetermined time period, the analyte
sensor is intermittently exposed to a biological sample (e.g.,
blood) and to a reference solution (e.g., an infusion solution
containing a defined amount of analyte), such as described
elsewhere herein. In some further embodiments, the processor module
is configured to and/or includes programming that intermittently
calculates a sensitivity of the analyte sensor based at least in
part on a signal obtained when the analyte sensor is exposed to a
biological sample (e.g., when blood is drawn back by the flow
control device, according to the flow profile). In some further
embodiments, the processor module is configured to and/or includes
programming that intermittently calculates a sensitivity of the
analyte sensor based at least in part on a signal obtained when the
analyte sensor is exposed to a reference solution (e.g., when the
flow control device infuses the reference solution, according to
the flow profile). In some further embodiments, the processor
module is configured to and/or includes programming that
intermittently calculates a sensitivity of the analyte sensor based
at least in part on a signal obtained when the analyte sensor is
exposed a biological sample and a signal obtained when the analyte
sensor is exposed a reference solution. For example, in some
embodiments, a subtracted signal, which is derived from the signals
obtained when the analyte sensor is exposed to the biological
sample and the reference solution, is used for calculation of
sensor sensitivity.
[1019] Sensor Stability Evaluation
[1020] It is known that many continuous analyte sensors, such as
but not limited to intravascular sensors, have an initial period of
sensor use after which the sensor signal becomes more stable and
substantially representative of the analyte concentration (e.g.,
where the current output from the sensor is stable relative to the
analyte level). This period of time is referred to as "break-in" or
"run in." Sensor break-in is a two-part process, including
electrochemical break-in of the electrodes (e.g., electroactive
surfaces) and membrane break-in (e.g., equilibration with the local
environment post implantation). In general, break-in is associated
with an exponential signal decay related to break-in of the
electroactive surfaces. It has been observed that in some sensor
system configurations, in addition to the exponential signal decay,
the non-enzyme working electrode signal response to blood exposure
is unstable for at least the first few cycles of system operation
(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles), depending
upon the flow profile and/or sensor configuration. In these
circumstances, to effectively remove baseline, in a dual-electrode
sensor, it is preferred that the error of the plus-enzyme and
no-enzyme working electrodes be within about .+-.10% of each other.
However, the additional instability observed on the no-enzyme
working electrode, in these circumstances, tends to increase the
difference between the errors (of the two working electrodes),
which causes inaccuracies (e.g., errors) in signal processing
(e.g., subtraction of the no-enzyme signal from the plus-enzyme
signal). While not wishing to be bound by theory, it is believed
that the non-enzyme electrode instability is caused, at least in
part, by the affects of biological noise and/or interferents on
some membrane systems. After break-in is complete, these problems
with the no-enzyme signal response are generally no longer
observed.
[1021] It has been observed that break-in is not a permanent
phenomenon. For example, it has been observed that when an
implanted (e.g., in use) sensor is turned off (e.g., de-energized),
after a time, the signal tends to begin destabilizing. In some
circumstances, sensor sensitivity (m) begins to deteriorate. For
example, calculated sensitivity values (m) may no longer meet the
criteria requirements of a sensitivity evaluation (e.g., fall
within the cone of possibility). Further, the longer the sensor
remains turned off, the less representative of the analyte
concentration the signal can become. However, the sensor can
break-in again, if it is re-energized (e.g., turned on again). The
length of this next break-in period depends, at least in part, on
how long the sensor was turned off. For example, if the sensor was
turned off for only 10 to 20 minutes, the break-in period could be
about 5-10 minutes. In another example, if the sensor was turned
off for three hours, a full hour or longer may be necessary for the
break-in process to be completed. Since it is preferred to use a
stable analyte sensor when measuring a host's analyte levels,
systems and methods for determining when the sensor (e.g., the
signal) is stable are provided in some embodiments.
[1022] Accordingly, in preferred embodiments, the system is
configured and arranged to evaluate sensor stability (e.g.,
determine when and/or if sensor break-in is complete).
Advantageously, evaluation of sensor stability enables improved
selection of sensitivity evaluation parameters, and thus improved
sensor calibration. For example, in some embodiments, when the
sensor is still breaking in, a wider set of sensitivity (e.g.,
drift) parameters are selected (e.g., to allow greater amounts of
drift, such as .+-.30%, .+-.40%, .+-.50%, .+-.60%, .+-.70%,
.+-.80%, .+-.90%, .+-.100%, .+-.200% or more sensitivity drift over
a given time period (e.g., 30-min, 1-hr, 2-hrs)). Then, when the
sensor signal has stabilized, a more narrow set of sensitivity
parameters are selected (e.g., .+-.5%, .+-.10%, .+-.15%, .+-.20%
sensitivity drift over about 5, 10 or 15 minutes). In yet another
embodiment, when the sensor is still breaking in (e.g., unstable),
the baseline can be determined by means other than subtraction of
the no-enzyme signal from the plus-enzyme signal, such as but not
limited to use of a priori information (e.g., in vitro and/or in
vivo) and/or external reference analyte values, as described
elsewhere herein. In a further embodiment, the system is configured
to prompt the user to enter an external reference value (e.g., a
finger-stick) about, near, at and/or after completion of break-in.
In some embodiments, the system is configured to intermittently
(e.g., 1, 2, 3, 4, 5, 6, 7, or more times every 10, 20, 30, 40, 50
or 60-minute or more) evaluate sensor stability, and to request an
external reference value if the sensor has not yet sufficiently
stabilized (e.g., if break-in is not yet complete). An average
break-in time can be empirically determined (e.g., a priori
information). In some embodiments, the system is configured to wait
a period of time associated with a predetermined break-in time, and
to begin evaluating sensor stability after that time period has
passed.
[1023] FIG. 15 is a flow chart illustrating sensor stability
evaluation, in one embodiment. At block 1500, a method for
determining a stability of an analyte sensor is provided, in one
embodiment.
[1024] At block 1502, sensor data is received from an analyte
sensor, such as by a data receiving module (also referred to as the
processor module) operably connected to the analyte sensor system
and configured to receive the sensor data from the sensor. In
preferred embodiments, the sensor is a dual-electrode sensor as
described elsewhere herein. For example, the analyte sensor
includes (1) a first working electrode (plus-enzyme electrode)
configured to provide first sensor data (e.g., a first signal),
which includes an analyte component and a baseline component, and
(2) a second working electrode (no-enzyme electrode) configured to
provide second sensor data (e.g., a second signal), which includes
a baseline component without an analyte component. In some
embodiments, the processor module is configured to and/or includes
programming that uses first sensor data and/or second sensor data,
when the dual-electrode sensor is exposed to a blood sample, to
evaluate sensor stability. In some embodiments, the processor
module is configured to and/or includes programming that uses the
first sensor data and/or the second sensor data, when the
dual-electrode sensor is exposed to an infusion solution, to
evaluate sensor stability. In some embodiments, the processor
module is configured to and/or includes programming that uses
subtracted signals to evaluate sensor stability. In some
embodiments, the processor module is configured to and/or includes
programming that uses only the second sensor data, received when
the sensor is exposed to blood and/or reference solution, in order
to determine when membrane break-in (e.g., membrane stabilization
between two working electrodes) is complete.
[1025] At block 1504, a stability of the analyte sensor is
determined, based at least in part on the second sensor data (e.g.,
data from the non-enzyme working electrode), such as via the
processor module. In some embodiments, the processor module is
configured to and/or includes programming that determines sensor
stability by evaluating a change in an amplitude of a plurality of
time spaced points (e.g., 2, 3, 4, 5, 10, 15, 20, 30, 40, 50 or 100
or more points) from the second sensor data, such as when the
sensor is exposed to a sample and/or an infusion solution. The time
space points are spaced by about 1, 3, 5, 10, 15, 20 or 30 minutes
to about 1, 1.5 or 2-hours or more, in some embodiments. For
example, in one embodiment, the processor module is configured to
compare the peak amplitudes from a plurality of measurement phases,
such as when the sensor is exposed to blood. In one exemplary
embodiment, the processor is configured to and/or includes
programming that compares the amplitude (e.g., peak) of a first
measurement (e.g., blood) phase to the amplitude of a second
measurement phase (e.g., the next measurement cycle). In another
exemplary embodiment, the processor is configured to and/or
includes programming that compares the amplitude of a first
calibration (e.g., exposed to calibration or reference infusion
solution) phase to the amplitude of a second calibration phase. In
another exemplary embodiment, the processor is configured to
compare a difference between the amplitudes of the calibration and
measurements phases of a first cycle (e.g., of a flow profile) to a
difference between the amplitudes of the calibration and
measurement phases of a second cycle. In yet another exemplary
embodiment, the processor is configured to use the subtracted
amplitudes (e.g., the plus-enzyme signal minus the no-enzyme
signal). In other embodiments, the processor module is configured
to and/or includes programming that compares a first point to a
second point, wherein the first point is measured when the analyte
sensor is exposed to the biological sample and the second point is
measured when the analyte sensor is exposed to the infusion
solution (e.g., a calibration, wash and/or infusion phase). In
other embodiments, the processor module is configured to and/or
includes programming that utilizes transient information, such as
described with reference to a step-change and FIG. 11, to evaluate
the sensor's stability.
[1026] In some embodiments, the processor module is configured to
and/or includes programming that evaluates sensor stability using
rate of change (ROC) information, such as but not limited to a
difference in ROCs between two measurement and/or calibration
phases of the second (no-enzyme) signal. In some embodiments, the
two measurement phases are consecutive (e.g., obtained during
consecutive cycles of the flow profile). However, in other
embodiments, the measurement phases are separated by one or more
measurement and/or calibration phases (e.g., cycles of the flow
profile) and/or spaced in time. For example, in some embodiments,
the cycles (e.g., during which the two measurement phases or two
calibration phases occur) are separated by 1, 2, 3, 4, 5, 6, 7 or
more (intervening) cycles; or the cycles (or phases) are separated
by 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120
minutes or longer. In some embodiments, the processor module is
configured to wait a period of time, such as but not limited to a
predetermined break-in time period (e.g., a period of time
approximately the length of an average break-in time for a
particular sensor configuration), prior to evaluating sensor
stability. In a preferred embodiment, the processor module is
configured to evaluate a plurality of ROCs, such as but not limited
to a series of 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more ROCs. For
example, in one embodiment, the processor module is configured
evaluate a first ROC (e.g., calculated for first and second
measurement phases) and a second ROC (e.g., calculate between
second and third measurement phases), relative to a threshold, and
so on. In some embodiments, the processor module is configured to
evaluate a plurality of ROCs within a window (e.g., moving or
non-moving) of calibration or measurement phases, relative to a
threshold.
[1027] In one exemplary embodiment, the processor module is
configured to and/or includes programming that evaluates sensor
stability (e.g., membrane break-in) using a moving predetermined
time period (e.g., a moving window) of ROCs calculated from the
second signal (e.g., from the no-enzyme electrode). In some
embodiments, the moving window encompasses 2, 3, 4, 5 or more
calculated ROCs. In some embodiments, the processor module is
configured to compare each calculated ROC and/or a difference
between two ROCs to a threshold, and to assign the ROC a flag
(e.g., +1, -1 or 0; categorized as pass/fail, etc.), based on the
comparison. For example, during the first hour of sensor use, the
expected ROC is about from .+-.30%, .+-.40% or .+-.50% per every 5,
10, 15 or 20 minutes to about .+-.60%, .+-.70%, .+-.80%, .+-.90%,
.+-.100%, .+-.200% or more per every 5, 10, 15 or 20 minutes;
whereas, during the second hour of sensor use, the expected ROC is
from about .+-.5% or less every 5, 10, 15 or 20 minutes to about
.+-.10%, .+-.15%, .+-.20% or .+-.25% more every 5, 10, 15 or 20
minutes. Accordingly, if the ROC exceeds the threshold, it is
flagged as +1. If the ROC falls below the threshold, then it is
flagged as -1. If, on the other hand, the ROC is within the
threshold, then it is flagged as zero (0). In some embodiments, the
processor module is configured to determine that the sensor is
substantially stable (e.g., break-in is complete) when the sum of
the flags is zero. For example, if the pre-determined time period
(e.g., a window) encompasses five (5) ROCs, the sum of the 5 flags
within the window should equal zero, for the sensor to be
considered stable. Preferably, the window is a moving window. For
example, in some embodiments, the processor is configured to slide
the window forward one ROC with each new cycle. In alternative
embodiments, the processor module is configured such that the sum
of the flags within the moving window must equal zero at least two
times before the sensor is determined to be substantially stable.
In still other embodiments, the processor is configured to evaluate
the flags, wherein the value of a plurality of sequential flags
(e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more flags) must equal zero
before the sensor is declared to be substantially stable. In some
embodiments, the threshold is associated with the expected profile.
In some other embodiments, the processor module is configured to
evaluate the first signal (e.g., the plus-enzyme signal) when a
sensor (dual-electrode or non-dual electrode) is exposed to
calibration solution, when determining sensor stability. However,
in other embodiments, the system is configured to evaluate sensor
stability using data received when the sensor is exposed to blood.
For example, in some embodiments of a dual-electrode sensor, the
processor module is configured to calculate the second signal ROCs
for two or more measurement cycles when the sensor is exposed to
blood.
[1028] In some embodiments, the sensor is considered to be stable
when it reaches a predetermined level (e.g., threshold) of
stability (e.g., the signal is stable and/or substantially
representative of the analyte concentration). Preferably, the
processor module is configured to and/or includes programming that
determines a predetermined (e.g., programmed) level of stability
has been reached, when an amplitude change of the second sensor
data meets one or more criteria. For example, in some embodiments,
the one or more criteria are designed (e.g., selected) to detect a
predetermined threshold (e.g., range) of plateau of the second
sensor data (see FIG. 11 for examples of plateaus (e.g., 1008
and/or 1010)). In some embodiments, the expected range of plateaus
is based at least in part on a priori information. Accordingly, in
some embodiments, the processor module is configured to determine
that the sensor is stable when a plateau of measured second sensor
data (e.g., the test data or waveform) is within the expected
range, such as but not limited to within about .+-.5%, .+-.10%,
.+-.15% or .+-.20% of the expected range. In addition to a moving
window, sensor stability can be evaluated using other statistical
techniques, such as but not limited to point-to-point comparisons,
evaluating a measured profile relative to an expected profile using
covariance, standard deviation, or r-value, and the like.
[1029] In preferred embodiments, the system is configured to and/or
includes programming that provides an output, such as via an output
module, also referred to as a processor module, in response to the
determination of the sensor's level of stability relative to a
predetermined threshold. For example, in some embodiments, the
processor module is configured to and/or includes programming that
displays (e.g., via the user interface) an analyte value,
information associated with sensor stability and/or other
information on a local and/or remote display of the user interface
in response to a determination of a sensor's stability meeting a
threshold (e.g., does the sensor stability meet the threshold or
not). In one exemplary embodiment, the processor module is
configured to and/or includes programming that displays a first
message when the sensor meets the threshold of stability, and a
second message when the sensor does not meet the threshold. In
another exemplary embodiment, the processor module is configured to
and/or includes programming that selects from a menu of messages,
symbols, or other indications, responsive to the level of sensor
stability determination. For example, in some embodiments, the
output includes an indication of at least one of a numeric
estimated analyte value, a directional trend of analyte
concentration, and a graphical representation of a plurality of
estimated analyte values. For example, the output can indicate a
request for reference analyte data. For example, if the sensor is a
glucose sensor, the system can request a finger-stick or YSI
reference analyte value. In another example, the system can request
an injection (e.g., into the tubing) of a defined amount of
analyte, such that the system can take a reference measurement as
the injected analyte contacts the sensor. In some circumstances,
other instructions are provided to the caretaker, in response to
the determination of the predetermined level of stability. For
example, an alert and/or alarm is sounded, such as by visual and/or
auditory components of the user interface.
[1030] As described above, the break-in process can occur at
various times during sensor use, such as during and/or after
start-up and after periods of disuse. Accordingly, in preferred
embodiments, the processor module is configured to and/or includes
programming that determines stability of the analyte sensor at
system start-up and/or after exposure of the sensor to blood and/or
a calibration, reference, or infusion solution. In some
embodiments, the processor module is configured to and/or includes
programming that determines (e.g., evaluates) stability of the
analyte sensor after a predetermined time period. For example, it
is known that, depending upon the sensor's configuration, break-in
can take from about 10, 20, 30 or 40 minutes to about 60, 90, 120
or 180 minutes or longer. For a given type of sensor, the average
break-in time (e.g., time period, length of time) can be determined
mathematically using a priori information. Accordingly, in some
embodiments, the system is configured to begin determining the
sensor stability after a predetermined time period (e.g., about
half, two-thirds, three-quarters or the entire average break-in
period, for that sensor configuration, has passed). In one
exemplary embodiment, an exemplary intravascular dual-electrode
glucose sensor can take about 1-hour to break-in. In this
embodiment, the system is configured to begin determining (e.g.,
evaluating) sensor stability at about 30, 40, 50 or 60-minutes or
longer. In a similar embodiment, analyte sensor stability is
determined after a system re-start, such as but not limited to in
circumstances when the sensor has been turned off for a period of
time. For example, the sensor may be turned off when moving the
patient, and then re-started; thus, the sensor's stability is
determined when the sensor system is re-started.
[1031] In one exemplary embodiment, the analyte sensor is a glucose
sensor, such as but not limited to a substantially continuous
glucose sensor described herein (see FIGS. 1A-1J, 2G-3I for
exemplary sensor configurations). For example, in some embodiments,
the sensor is a component of the integrated system depicted in FIG.
6, in some embodiments. Preferably, the system (e.g., the processor
module is) configured to and/or includes programming that
determines the glucose sensor's stability. For example, the system
is configured to begin determining the glucose sensor's stability
after about 30, 40, 50, 60 or 70 minutes of implantation. In some
embodiments, the glucose sensor is a dual-electrode continuous
glucose sensor, such as a sensor configured for implantation into a
peripheral vein of the host, wherein the sensor's stability is
determined using a plurality of time-spaced sensor data points
received from the enzymatic working electrode and/or the
non-enzymatic working electrode, such as but not limited to when
the sensor is exposed to blood samples (e.g., during a measurement
phase of the flow profile) and/or a calibration phase. Determining
the glucose sensor's stability can include evaluating the sensor's
stability relative to one or more predetermined criteria, such as
but not limited to a profile range (e.g., within about .+-.5%,
.+-.10%, .+-.15% or .+-.20% of an average profile) generally
observed for that particular type of glucose sensor. In preferred
embodiments, the glucose sensor system is configured to determine
the sensor's stability iteratively and/or periodically. In a
further embodiment, the glucose sensor system is configured to
determine the sensor's stability after re-start, such as after a
period of disuse, as described herein.
[1032] Diagnostics and Fail-Safes
[1033] In some embodiments, the system includes programming
configured to diagnose a condition of at least one of the sensor
and the host responsive to calibration information. In some
embodiments, the system intermittently or continuously determines
at least some calibration information (e.g., sensitivity
information, b.sub.offset, and the like), each time the sensor is
exposed to a reference solution and/or a biological sample.
[1034] In one embodiment, systems and methods are configured to
find a plateau and/or stable window of data in response to exposure
of the sensor to at least one of a reference solution and a
biological sample. In some embodiments, if the system cannot find
the plateau and/or stable window of data, the system is configured
to "fail-safe;" for example, in some circumstances, a lack of
plateau and/or stable window of data may be indicative of dilution
and/or mixture of the reference solution (e.g., calibration
solution) with the biological sample (e.g., blood), and/or
interruption/disruption of expected/desired fluid flow.
Additionally, in some circumstances, a lack of plateau and/or
stable window of data may be indicative of interfering species in
the signal.
[1035] In general, the term "fail-safe" includes modifying the
system (e.g., the processor module) processing and/or display of
data in some manner responsive to a detected error, or unexpected
condition, and thereby avoids reporting and/or processing of
potentially inaccurate or clinically irrelevant analyte values.
[1036] In another embodiment, systems and methods are configured to
process a signal responsive to exposure of the signal to a
reference and/or biological sample to determine whether the signal
is within a predetermined range; if the signal falls outside the
range, the system is configured to fail-safe.
[1037] In some embodiments, systems and methods are configured to
determine calibration information including sensitivity
information, wherein the system includes programming configured to
diagnose an error responsive to a change in sensitivity above a
predetermined amount. For example, in a sensor system as described
in more detail with reference to the exemplary embodiment of FIGS.
8A to 8C, the system can be configured to determine a sensitivity
value during each calibration phase; and wherein the system can be
configured to fail-safe when the sensitivity of a calibration phase
differs from the previously stored sensitivity by more than a
predetermined threshold. In this exemplary embodiment, fail-safe
can include not using the sensitivity information to update
calibration, for example. While not wishing to be bound by theory,
the predetermined threshold described above allows for drift in the
sensitivity of the sensor, but prevents large fluctuations in the
sensitivity values, which may be caused by noise and/or other
errors in the system.
[1038] In some embodiments, systems (including programming) and
methods are configured to diagnose error in the sensor system by
ensuring the sensor signal (e.g., raw signal of the reference
solution(s)) is within a predetermined range. In some embodiments,
the sensor signal must be within a predetermined range of raw
values (e.g., counts, current, etc). In some embodiments, one or
more boundary lines can be set for a regression line drawn from the
calibration phase. For example, subsequent to performing
regression, the resulting slope and/or baseline are tested to
determine whether they fall within a predetermined acceptable
threshold (boundaries). These predetermined acceptable boundaries
can be obtained from in vivo or in vitro tests (e.g., by a
retrospective analysis of sensor sensitivities and/or baselines
collected from a set of sensors/patients, assuming that the set is
representative of future data). U.S. Patent Publication No.
US-2007-0197889-A1, which is incorporated herein by reference in
its entirety, describes systems and methods for drawing boundaries
lines. In some embodiments, different boundaries can be set for
different reference solutions.
[1039] In some embodiments, systems and methods are configured for
performing diagnostics of the sensor system (e.g., continuously or
intermittently) during exposure of the sensor to a biological
sample, also referred to as the measurement phase, for example,
such as described in more detail above with reference to FIGS. 8A
to 8C. In some embodiments, diagnostics includes determination
and/or analysis of b.sub.offset. In some embodiments, systems and
methods are provided for comparing sequential b.sub.offset values
for sequential measurement phases. In some embodiments, the system
includes programming configured to diagnose an error and fail-safe
responsive to a change in the b.sub.offset above a predetermined
amount. In some embodiments, the system includes programming
configured to re-calibrate the sensor responsive to changes in the
b.sub.offset above a predetermined amount. In some embodiments, the
system includes programming configured to detect an interfering
species responsive to a change in the b.sub.offset above a
predetermined amount.
[1040] In some embodiments, the system includes programming
configured to diagnose a condition of the host's metabolic
processes responsive to a change in b.sub.offset above a
predetermined amount. In some embodiments, the system includes
programming configured to display or transmit a message associated
with the host's condition responsive to diagnosing the condition.
While not wishing to be bound by theory, it is believed that
changes in b.sub.offset can be the result of an increase (or
decrease) in metabolic by-products (electroactive species), which
may be a result of wounding, inflammation, or even more serious
complications in the host; accordingly, changes in b.sub.offset can
be useful in diagnosing changes in the host's health condition.
[1041] In some embodiments, the system includes programming
configured to detect sensor error, noise on the sensor signal,
failure of the sensor, changes in baseline, and the like,
responsive to a change in b.sub.offset above a predetermined
amount.
[1042] In some embodiments, the system includes programming
configured to determine a time constant of the sensor. One method
for calculating a time constant for a sensor includes determining
an impulse response to a step change, wherein time at the peak of
the impulse response represents a time constant for the sensor.
While not wishing to be bound by theory, it is believed that the
time constant determined from the peak of the impulse response
should remain substantially the same throughout the life of the
sensor. However, if a shift in the time constant (between step
changes and their associated impulse response curves) above a
predetermined range is detected, it can be indicative of an
unexpected sensor condition or error, for example. Accordingly, by
comparing time constants from a plurality of impulse response
curves (derived from a plurality of step responses), programming
can be configured to diagnose a sensor condition or error and
initiate programming (e.g., fail-safe), accordingly.
[1043] Accordingly, the system can "fail-safe," including
performing one or more of the following fail-safe responses:
temporarily or permanently suspending (e.g., discontinuing) display
of analyte data, updating calibration or re-calibrating the sensor,
requesting external reference values, using external reference
value(s) as confirmation of a detected condition, using external
reference value(s) to update calibration or re-calibrate the
sensor, shutting the system down, processing the sensor data to
compensate for the change in b.sub.offset, transmitting one or more
messages to the user interface or other external source regarding
the sensor condition, and the like.
[1044] In preferred embodiments, the sensor electronics include a
fail-safe module that is configured to detect a system malfunction.
The fail-safe module can be configured to detect a variety of
system malfunctions. For example, the fail-safe module can be
configured to detect electrical malfunctions, malfunctions of the
system fluidics, malfunctions of the sensor, and/or the like. For
example, the system electronics can be configured to test and/or
track the functions of different system components, and to
intelligently recognize aberrant changed in such functions as
possible malfunctions.
[1045] In some embodiments, the fail-safe module is configured to
detect electrical malfunctions, such as but not limited to short
circuit and electrical malfunction associated with start-up and/or
sensor break-in. For example, it is known that an I/R drop across
an electrochemical sensor's working electrode(s) generally occurs
during use. The I/R drop can be monitored for changes, which can be
indicative of an electrical malfunction. Similarly, during use of
an analyte sensor in an intravascular system, wherein the sensor is
periodically/alternately exposed to at least one reference solution
and a blood sample, the generated signal is expected to rise and
fall in a regular fashion, for example a recognizable wave-form
pattern including peaks and valleys. For example, when the enzyme
sensor is exposed to blood, the rate of the step-response indicates
the change in glucose from calibration solution to blood. The
plateau of the response also indicates the glucose concentration
(although the plateau generally indicates the absolute glucose
concentration, not the change in glucose concentration).
Accordingly, the fail-safe module can be configured to monitor the
pattern of step-responses (e.g., over time) for substantial
changes/deviations, which can be indicative of electrical
malfunctions. For example, in some circumstances, the signal can
"rail" or "zero," wherein the signal rapidly changes to a
non-physiological analyte value and remains relatively stable at
that non-physiological value for a period of time. In some
circumstances, the rapid change in value occurs at a rate that is
also not physiologically possible. In some circumstances, a
comparison of the rate-response (e.g., transient/kinetic
information) versus plateau response (e.g., steady state
information) of each blood measurement can be used as an indicator
of sensitivity drift. Similarly, in some embodiments, comparison of
rate-response versus plateau response on a non-enzymatic
electrode/sensor when expose to blood can provide information
related to the sensor's response to non-glucose species in the
sample, which can be used to determine if and/or when to
fail-safe.
[1046] In some embodiments, the fail-safe module is configured to
detect fluidics malfunctions, which can include a malfunction of
any part of the system configured to contact and/or move a fluid.
For example, the vascular access device (catheter) can become
occluded, such as due to blood clotting or pressing the in vivo
orifice (e.g., catheter tip) against a vessel wall such that fluid
cannot move in an out of the vascular access device. In some
circumstances, the tubing can become kinked, the host can move his
or her arm such that the catheter becomes bent, bubbles may get
into the system, and/or the flow control system can malfunction
(e.g., not metering fluid flow into the host or not withdrawing
blood samples as it was programmed to do), such that washing,
calibration, sample collection and the like are not performed as
programmed. For example, the sample can become diluted with
calibration solution, there may be clotting on a portion of the
sensor, and the like. In one exemplary embodiment, the fail-safe
module is configured detect fluidics malfunctions by monitoring the
pattern of signal increases/decreases generated on the working
electrode(s), to detect periods of time during which the signal
does not follow an expected waveform (e.g., using known waveform
analysis methods and/or pattern recognition algorithms), such as
when the signal hits upper and/or lower limits. For example, if the
signal zeros for a period of time, the fluidics system may be
unable to withdraw a blood sample due to kinking of the tubing or
occlusion of the catheter. In another example, the signal on the
working electrode(s) may stop going back down when the tested blood
sample should be re-infused into the host and the sensor should be
contacted with wash/reference solution, which is indicative of a
malfunction of expelling the used sample, washing the sensor, and
the like. For example, if the catheter becomes occluded by a blood
clot, the flow control system will be unable to meter fluid through
the catheter.
[1047] In some embodiments, the fail-safe module is also configured
to detect malfunctions of the analyte sensor. For example, a sensor
malfunction includes but is not limited to noise on the signal,
drift of sensor sensitivity and/or baseline, a broken component of
the sensor, blood clotting on a portion of the sensor, and
cross-talk, as described in more detail elsewhere herein.
[1048] In preferred embodiments, the fail-safe module is further to
evaluate a detected malfunction against a criterion. One or more
criteria can be preprogrammed (including reprogrammed) into the
system, such as be a host, a caretaker of the host, and/or the
manufacturer. For example, in some embodiments, one or more
criteria could be selected from a menu/list of criteria, or
manually programmed into the system. Available criteria can be
responsive to the different types of malfunctions can occur and/or
a user-perceived level of severity and/or urgency.
[1049] After a system malfunction has been detected, the fail-safe
module is configured to provide an alert, an alarm and/or an
instruction, such as to the host and/or a caretaker of the host.
For example, the system can be configured to provide an auditory
alarm (e.g., beeps, busses, siren, pre-recorded voice message,
etc.), a visual alert (e.g., blinking or flashing lights or display
screen), a tactile alert (e.g., vibrating), transmitting
alerts/instructions to a remote location, such as a nurse's station
or a doctor's phone/PDA, and the like.
[1050] As a non-limiting example, a method is provided for
detecting system malfunctions via the processing of the data of a
continuous analyte sensor implanted in a host's circulatory system.
As described elsewhere herein, the continuous analyte sensor is
configured to generate a signal associated with an in vivo analyte
concentration when the sensor is implanted in the host.
Additionally, the sensor electronics includes a fail-safe module
configured to detect a system malfunction. Accordingly, the method
includes exposing the sensor to a sample from the host's
circulatory system and detecting a malfunction of the system, such
as but not limited to an electrical malfunction, a fluidics
malfunction, and/or a sensor malfunction. In some embodiments, an
equilibrium analysis and/or a kinetic analysis of received
data/signal is performed. As described elsewhere herein, the data
include steady state (e.g., sensitivity and/or baseline
information) and/or transient state information, which can be
evaluated/analyzed to provide alerts, alarms and/or
instructions.
[1051] As described herein, the system (e.g., the processor module
and/or fail-safe module) can be configured to analyze steady state
and or transient state information generated during the step-up
response of the sensor, such as during the switch from blood to
reference solution and vice versa, also referred to as waveform
analysis (for example, using pattern recognition algorithms, and
the like). For example, by analyzing the step-up waveform of a
dual-electrode sensors non-enzymatic working electrode, the quality
of blood sample aspiration can be evaluated (e.g., fluidics).
Similarly, by analyzing the step-down waveform of the sensor's
non-enzymatic working electrode, the quality of washing can be
evaluated (e.g., fluidics). As another example, analysis of
direction of the step-up response of the plus-enzyme working
electrode upon exposure to blood can used to evaluate calibration
accuracy.
[1052] System Diagnostics
[1053] During operation of the integrated system, wherein the
system includes a continuous analyte sensor implanted in the host's
circulatory system and a flow control device (e.g., FIG. 6-7),
system artifacts, such as but not limited to distortion of
calibration and analyte measurement waveforms can occur
unexpectedly, for a variety of reasons. For example, anything that
affects IV tubing can cause a fluidics malfunction, such as the
host leaning on the IV tubing, or a blood clot fouling the sensor
or occluding the catheter and/or vessel. To some extent, sensor
calibration and analyte concentration determination are dependent
upon the quality of the calibration and measurement waveforms,
respectively. For example, a good quality waveform can be an
indicator that the sensor can be accurately calibrated with the
data comprised in that waveform and/or in a substantially
time-corresponding waveform. However, it has been observed that in
some circumstances, a signal waveform will be of poor quality
(e.g., not representative of the system's function), and the data
contained in that waveform is likely to be unsuitable for
subsequent calculations, processes, and the like. For example, a
poor quality the waveform can be an indicator that analyte
measurements may not be accurate. Such a circumstance could be
detrimental to the host's health. In such circumstances, not using
(e.g., "throwing out" or disregarding) the poor quality signal
waveform and its associated data, for calculating an analyte
concentration, maintains sensor accuracy and saves time.
Accordingly, preferred embodiments provide systems and methods for
performing system diagnostics on the analyte sensor system, for
example, such that the quality of a waveform is evaluated prior to
use of data comprised in the waveform for sensor calibration and/or
determination of analyte calibration.
[1054] FIG. 16 is a flow chart illustrating system diagnostics, in
one embodiment. At block 1600, a method for performing a diagnostic
of an analyte sensor system is provided, wherein the method
includes providing a sensor system, which includes an analyte
sensor and a flow control device configured to intermittently
expose the analyte sensor to a biological sample and to an infusion
solution, wherein the analyte sensor includes (1) a first working
electrode configured to provide a first signal (e.g., plus-enzyme
working electrode) including an analyte component and a baseline
component and (2) a second working electrode configured to provide
a second signal (e.g., second sensor data) including a baseline
component substantially without an analyte component (e.g.,
no-enzyme working electrode), and evaluating the sensor system
based at least in part on the second signal. Suitable
dual-electrode continuous analyte sensor systems, such as those
including twisted or bundled working electrodes or with working
electrodes located within the fluid coupler, are described in
detail elsewhere herein, such as but not limited to the sections
entitled "Dual-Electrode Analyte Sensors," "Multi-Sensor
Apparatus," and "Sensor Configurations for Equivalent Measurement
of Noise Signals at the Two Working Electrodes." However, other
dual electrode analyte sensors can be used, such as but not limited
to those described in U.S. Pat. No. 6,175,752 and U.S. Patent
Publication No. US-2008-0119703-A1, U.S. Patent Publication No.
US-2008-0108942-A1, and U.S. Patent Publication No.
US-2008-0200789-A1, each of which is incorporated herein by
reference in its entirety.
[1055] In preferred embodiments, the processor module is configured
to and/or includes programming that evaluates the second signal
(e.g., the no-enzyme signal) for an expected shape and/or pattern
when the sensor is exposed to a biological sample and/or to an
infusion solution. For example, in some circumstances, this is done
to determine if the system fluidics (e.g., draw-back and infusion)
are functioning properly. In some embodiments, the system is
configured such that the flow profile includes a measurement phase
and an infusion phase. During the measurement phases, the flow
control device is configured to draw-back a sample, such that the
sample contacts the sensor. It has been observed that during a
measurement phase, the second signal (e.g., no-enzyme working
electrode) waveform tends to rise in a monotonic manner, if the
draw-back was successful. It has also been observed (e.g., over
numerous in vitro and in vivo experiments) that during infusion
(e.g., re-infusion of the drawn-back sample, infusion of
calibration, a calibration period/phase), the second signal
waveform tends to fall (e.g., decline) in a monotonic manner, if
the infusion was successful. Deviation from these observed patterns
may indicate that the draw-back or infusion was not successful,
and, therefore, data comprised in the waveform may be unsuitable
for use in some calculations.
[1056] In one exemplary embodiment, the processor module is
configured to and/or includes programming that evaluates the second
signal to determine a success of drawing back a biological sample
from a host's circulatory system to the sensor (e.g., to contact
the sensor). For example, in some embodiments, the system is
configured to use data contained in the measurement waveform to
calculate the analyte concentration, if it (the system, processor
module) determines that the draw-back was successful. On the other
hand, the system is configured to disregard/not use data comprised
in the measured waveform for subsequent calculations (e.g., analyte
concentration, sensor calibration, etc.), if it is determined that
the draw-back was unsuccessful. In a further embodiment, the system
is configured to display an analyte value measured during the
biological sample draw-back in response to determining that the
draw-back of sample was successful. In another exemplary
embodiment, the system is configured to evaluate the signal to
determine if an infusion was successful. In some embodiments, a
successful infusion includes at least one of re-infusing the
biological sample into the host, washing the sensor (e.g., removing
a sufficient amount of sample such that substantially accurate data
can be obtained during the next sample draw-back without
interference from components from the current sample draw-back) and
infusing an amount of infusion solution. For example, in some
embodiments, determining a successful infusion includes displaying
an analyte value measured in a biological sample after the infusing
the infusion solution in response to a determination of a
successful infusion.
[1057] At block 1602, the analyte sensor is intermittently exposed
to a biological sample and to an infusion solution. For example,
the flow profile can include analyte measurement and calibration
phases, such that the flow control device intermittently draws back
blood samples that contact the sensor and infuses at least one
reference solution, as described elsewhere herein.
[1058] At block 1604, the system receives a first signal (e.g., the
signal from the first working (e.g., plus-enzyme, enzymatic)
electrode) including analyte and baseline (e.g.,
non-analyte-related) components and a second signal (e.g., the
signal from the second working electrode (e.g., the non-enzymatic,
no-enzyme electrode) including a baseline component without an
analyte component. As is understood in the art, the signal includes
a waveform, which is referred to as the "signal waveform" and/or
the "test waveform." For example, when the signal (e.g., in counts)
is plotted against time, the graph looks like a wave. The waveform
is associated with the intermittent (e.g., alternating, cyclical)
exposure of the sensor to blood and infusion solution. The
iterative (e.g., cyclical, periodic) intermittent exposure of the
sensor to blood and infusion solution can generate a plurality of
waveforms. If the signal waveform is generated during a calibration
phase of the flow profile (e.g., during exposure of the sensor to a
calibration solution), also referred to herein as a "calibration
signal waveform," then at least a portion of the data generated can
be used for calibrating the sensor. If the signal waveform is
generated during a measurement phase (e.g., during exposure of the
sensor to a sample of the host's blood), also referred to herein as
a "measurement signal waveform," then at least a portion of the
data generated can be used for determining the host's blood analyte
concentration.
[1059] At block 1606, the processor module is configured to and/or
includes programming that evaluates the system, based at least in
part on the second signal (e.g., the no-enzyme signal of the
non-enzymatic (e.g., second) working electrode). Since the signal
generated by the no-enzyme working electrode includes baseline but
substantially no analyte signal component, the shape (e.g.,
pattern) of the signal waveform generated is associated with (e.g.,
diagnostic of) the quality of the system's function (e.g., how well
the system is functioning). For example, fluidics and sensor
function problems are reflected in the waveform as a deviation from
an expected pattern, such as but not limited to an average waveform
generally observed when a system is in use.
[1060] The signal waveform can be evaluated using a variety of
methods. In some embodiments, the processor module is configured to
and/or includes programming that evaluates the signal waveform
(e.g., of the second signal) by evaluating the signal waveform for
an expected shape and/or pattern when the sensor is exposed to a
biological sample and/or to the infusion solution (e.g., a
hydration, reference, and/or calibration solution). For example, it
has been observed, through numerous in vitro and in vivo
experiments, that the second signal waveform tends, in a
characteristic way, to rise (e.g., increase) when the sensor is
exposed to sample (e.g., blood) and to fall (e.g., decrease) when
the sensor is exposed to an infusion solution. In some embodiments,
the processor module evaluates the signal waveform by evaluating a
similarity and/or correlation between the signal waveform and a
waveform template. In a further embodiment, a second signal
waveform is compared to this expected shape (e.g., pattern), such
as by visual inspection or similar means. For example, the second
signal waveform and the expected waveform pattern can be graphed
together, and then observed and/or evaluated to determine if they
have a similar shape, if they are close together, if they
substantially overlap (e.g., overlap by about 80%, 85%, 90%, or
95%), and the like. In one exemplary embodiment, the system is
configured to use at least some of the data from the second signal
waveform in subsequent mathematical processes and/or calculations
(e.g., sensor calibration, analyte concentration calculation) if
the second signal waveform is substantially similar to the expected
shape (e.g., pattern; the signal waveform is of sufficiently and/or
substantially high quality). In a further embodiment, the system is
configured to use at least some of the first signal waveform data
(e.g., plus-enzyme electrode) for determining the analyte
concentration, calculating sensor sensitivity, calibrating the
sensor, and/or the like, when the second signal waveform is
substantially similar to an expected shape (e.g., pattern) and/or
meets one or more criteria (e.g., falls within a threshold). If the
second signal waveform is not sufficiently and/or substantially
similar to the expected shape (e.g., pattern) and/or does not meet
the one or more criteria (e.g., it is of lower quality), then the
system is configured to disregard (e.g., not use, throw out) the
second signal waveform data for other purposes, such as subsequent
calculations. In a further embodiment, the system is configured to
disregard the first signal waveform data (e.g., plus-enzyme
electrode) when the second signal waveform is not substantially
similar to the expected shape (e.g., pattern) and/or exceeds the
threshold.
[1061] In preferred embodiments, the processor module is configured
to and/or includes programming that uses mathematical methods to
evaluate a signal waveform. In some embodiments, one or more
waveforms are evaluated using correlation waveform analysis (e.g.,
cross-correlation). Preferably, correlation waveform analysis
quantifies a correlation and/or similarity of corresponding points
(e.g., of a measured waveform vs. a waveform template) for a
variance, which provides an indication or measurement associated
with directional correlation of the points. Additionally or
alternatively, waveform analysis can include systems and methods
for quantifying overlap of the corresponding points, namely, an
amplitude or amount of difference between the measured waveform vs.
a waveform template. In some preferred embodiments, waveform
analysis ensures normalization of data such that maximum and
minimum amplitudes are equivalent for comparison purposes. In
general, any of the waveform analysis described herein can be
performed on actual waveforms (signal) or transforms of the
waveform, as is appreciated by one skilled in the art.
[1062] In some embodiments, a level of quality of the signal
waveform is evaluated (e.g., a level of reliability). In some
further embodiments, the system is configured to perform one or
more tasks, such as calibrating the sensor, displaying information,
or the like, responsive to the level of quality of the signal
waveform, such as described herein. In some embodiments, the level
of reliability is classified as pass or fail, good versus bad,
acceptable versus not acceptable. In some further embodiments, the
system is configured to perform a task when the waveform is
classified as pass, acceptable or the like, such as described
herein. In some further embodiments, the system is configured to
perform another task or do nothing when the waveform is not
classified as pass, acceptable, or the like (e.g., the waveform is
classified as failed, not acceptable, etc.).
[1063] In some embodiments, when the second signal waveform is
compared to an expected shape (e.g., pattern), a similarity and/or
correlation of the second signal waveform to a waveform template
(e.g., seed template) is evaluated. In some embodiments, the
waveform template is based at least in part on a priori
information. For example, a waveform template (for a measurement or
a calibration phase) is generated (e.g., created, calculated,
provided, determined, and/or formed) by integrating a plurality of
previously generated second signal waveforms. Preferably, a
waveform template is generated from a plurality of second signal
waveforms obtained during previous in vitro and/or in vivo
experiments (e.g., system uses). While in some embodiments, about
2, 5, 10, 20, 30, 40 or 50 second signal waveforms to about 60, 70,
80, 90 or 100 second signal waveforms are integrated to generate
(e.g., produce, form) the waveform template, in other embodiments,
hundreds or thousands of second signal waveforms are integrated to
generate a waveform template (e.g., seed template). In some
embodiments, a waveform template is generated from previous sensor
sessions from an individual host, such as to provide an adaptive
waveform template.
[1064] In some embodiments, the waveform template contains
information specific to the sensor system in use, in addition to a
priori information. For example, in some embodiments, the waveform
template is based at least in part on a second signal waveform
measured by the system (e.g., the system in use). Preferably, the
processor module is configured to and/or includes programming that
updates the template waveform (e.g., with the second signal
waveform) when a similarity and/or correlation between the (second)
signal waveform and the waveform template meets one or more
criteria (and/or fall within a threshold). For example, if the
second signal waveform substantially correlates with (e.g., at
least about 80%, 85%, 90% or 95%) the (current) waveform template,
the signal waveform is used to update the waveform template, to
generate an updated waveform template (e.g., newest, latest version
of, most recently updated), also referred to herein as an "adaptive
template." Conversely, if the second signal waveform does not meet
the one or more criteria, the system is configured to not integrate
the second signal waveform with the waveform template (e.g., the
system can "throw out" the poor quality or bad waveform). In some
embodiments, a similarity of the second signal waveform to the
template is evaluated by plotting the second signal waveform (e.g.,
the waveform just measured) with the waveform template, wherein the
processor module is configured to and/or includes programming that
determines a correlation (or deviation) of the two waveforms in
shape and/or amplitude. In other embodiments, the second signal
waveform is mathematically correlated with the template waveform,
to determine how they correlate (or deviate). While not wishing to
be bound by theory, it is believed that an adaptive waveform
template provides system diagnostics adapted for each host and use
of the system. It should be noted herein that an initial waveform
template is used when the sensor system is started up, with
subsequent use of the adaptive template thereafter. Accordingly, in
some embodiments, an adaptive template is substituted for a
waveform template as soon as the adaptive template is
generated.
[1065] In some embodiments, the processor module is configured to
and/or includes programming that detects a level of interferent in
the biological sample (e.g., such as described elsewhere herein).
In some embodiments, the waveform template is updated when the
level of interferent meets one or more criteria. For example, in
some embodiments, the processor module is configured to update the
waveform template when substantially no interferent (e.g., less
than about 20%, 10%, 5%, 4%, 3%, 2% or 1% of the signal) is
detected. In this embodiment, if interference is detected on the
signal (e.g., above 1, 2, 3, 4, or 5% of the signal), then the
signal waveform is not used to update the template. If, however,
interference is not detected on the signal (or is less than or
equal to about 5%, 4%, 3%, 2% or 1% of the signal), then the
processor module updates the waveform template (or the adaptive
template) with signal waveform. In some embodiments, a lower level
of interferent on the signal, such as 15%, 10%, 5%, 4%, 3%, 2% or
1% or less of the signal is acceptable. Accordingly, if the level
of interferent detected is less than or equal to the criteria
(e.g., within the threshold) then the waveform template (or the
adaptive template) is updated with the signal waveform. If the
level of interferent does not meet the criteria (e.g., exceeds the
threshold) then the waveform template (or adaptive template) is not
updated.
[1066] In some embodiments, evaluating the sensor system includes
detecting an interferent by evaluating an amplitude, a change in
amplitude, the signal waveform and/or a change in the signal
waveform (e.g., of the second signal) when the sensor is exposed to
the biological sample. In some embodiments, interferent detection
is further based at least in part on a calibrated analyte value. In
one exemplary embodiment, the system is configured to look for a
change in analyte concentration (e.g., amplitude) above a threshold
(e.g., exceeding a criterion) in combination with evaluating a
second signal waveform.
[1067] In preferred embodiments, the processor module is configured
to and/or includes programming that controls a display of the
sensor system based at least in part on a level of interferent
detected. For example, in some embodiments, the processor module is
configured to not display an analyte value measured in a biological
sample in response to an amount (e.g., level) of interferent
detected on the second signal based on one or more criteria. For
example, when the detected interferent on the no-enzyme working
electrode exceeds a predetermined threshold (e.g., an amount of the
signal, such as but not limited to 5, 10, 15, 20, or 25% or more of
the signal), the analyte value is not displayed. In an exemplary
embodiment, what is displayed is responsive to the level of
interferent detected. For example, if the level does not meet the
criteria, then a first indication (e.g., message or value) is
displayed; if the level meets the criteria, then a second
indication is displayed; if the level exceeds the criteria, then a
third indication is displayed. In another example, if the level of
interferent detected meets a first criteria, then an indication or
message associated with the first criteria is displayed; if the
level of interferent detected meets a second criteria, then an
indication or message associated with the second criteria is
displayed; and the like.
[1068] In some embodiments, processor module is further configured
to process the first signal and the second signal to obtain a
subtracted signal, wherein the step of processing is based at least
in part on the level of interferent on the sensor system. For
example, in some circumstances, the signal is processed to remove
offset of the baseline and/or compensate for a measured interferent
(e.g., one or more interfering species) on the signal, and/or the
like, such as described elsewhere herein.
[1069] In a further embodiment, the processor module is configured
to fail-safe when the no-enzyme signal and the analyte
concentration (or change in analyte concentration) do not meet one
or more criteria.
[1070] As described above, the waveform of the non-enzyme working
electrode (e.g., the second signal) has a characteristic pattern.
In some embodiments, a characteristic pattern includes monotonicity
or substantial monotonicity. The term "monotonicity" 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 are not to be
limited to a special or customized meaning), and refers without
limitation to a quality of a sequence or function, wherein it is
either substantially increasing or substantially decreasing in
value, such as but not limited to about 80%, 85%, 90%, 95% or more
of the time. Thus, a measurement signal waveform generally smoothly
rises, while a calibration signal waveform generally falls
smoothly. Accordingly, in some embodiments, the step of evaluating
the sensor system includes evaluating a monotonicity of the signal
waveform (e.g., is the signal waveform monotonic or does is contain
bump, jumps, blips, etc.). In some embodiments, the system is
configured to evaluate the monotonicity of the signal waveform by
performing cross-correlation of the signal waveform with a waveform
template. If the signal waveform is not monotonic, is will not
correlate well with the waveform template. In other embodiments,
the monotonicity of the signal waveform is evaluated by performing
a time-series analysis, or the like.
[1071] In some embodiments, the processor module is configured to
and/or includes programming that evaluates a reliability of the
system. For example, in some embodiments, the signal waveforms
generated over a period of time (e.g., a window), such as 5, 10,
15, 20 or 30 minutes or longer, are evaluated, such as to ensure
that the waveforms are substantially consistent over that period of
time. In some embodiments, the window of waveforms to be evaluated
is a moving window, encompassing the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
20 or 30 (or more) most recently generated second signal
waveforms.
[1072] In some embodiments, evaluating the reliability of the
system includes determining a level of reliability of the sensor
system, such as by comparing an amplitude, a change in amplitude, a
signal waveform and/or a change in a signal waveform of the second
signal to one or more criteria. In some embodiments, the one or
more criteria include an expected waveform shape and/or pattern.
For example, if the second signal waveforms within a window are
substantially monotonic, within a predetermined range of
correlation, then the system is configured determine a level of
reliability (e.g., reliable or "pass"). Conversely, if the second
signal waveforms within a window are outside the predetermined
range of monotonicity and/or correlation, the system is configured
determine a reduced level of reliability (e.g., not reliable or
"fail"). A level of 100% reliability of the sensor system can be
defined using known methods, including time-series analysis,
standard deviation, variance, covariance, and/or the like.
Accordingly, in some embodiments, the level of reliability of the
sensor system is 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% or more
as compared to a 100% level as defined by the methods described
above, for example. Depending upon the system configuration,
various levels of reliability may be acceptable. For example, a low
level of reliability may be acceptable for a first system
configuration while only a high level of reliability may be
acceptable for a second system configuration. Furthermore, in some
embodiments, the system is configured to perform one or more
functions or tasks, such as but not limited to calculating a value,
displaying information, updating a template, and the like,
depending upon the level of reliability, wherein the acceptability
of the reliability is associated with the system configuration.
[1073] In other embodiments, evaluating the reliability of the
system includes classifying a signal waveform, such as by comparing
an amplitude, a change in amplitude, a signal waveform and/or a
change in a signal waveform of the second signal to one or more
criteria. For example, a signal waveform can be classified as
"pass" or "fail," if it meets the one or more criteria. For
example, in some embodiments, the system is configured to pass the
signal waveform when it correlates with the template waveform by at
least 50, 55, 56, 70, 75, 80, 85, 90 or 95%. The system can be
configured to classify a signal waveform as "pass" or "fail" using
other mathematical methods, described elsewhere herein. In some
embodiments, the system is configured to use at least some of the
data in the signal waveform (e.g., second signal) and/or data in a
time-corresponding signal waveform (e.g., first signal) for
subsequent mathematical processes, such as calibrating the sensor,
calculating the analyte value and the like, when the signal
waveform is classified (e.g., declared) as "pass," such as
described herein. Conversely, in some embodiments, the system is
configured to not use the data when the signal waveform is
classified as "fail."
[1074] In some embodiments, the system is further configured to
control a display of the sensor system based at least in part on
the level of reliability of the sensor system (e.g., pass or fail).
For example, if the system is determined to be reliable, then an
analyte value is displayed to the user. If, on the other hand, the
level of reliability does not meet one or more criteria, then the
system is configured to respond in another way, such as not
displaying an analyte value, sounding an alert or alarm, requesting
input of information by the user, and the like. In a further
embodiment, the system is configured to modify a subtraction of the
second signal from the first signal (e.g., processing associated
with the subtraction) based at least in part on the reliability of
the sensor system.
[1075] In some embodiments, the system is configured to evaluate a
portion of a second signal waveform, rather than the entire
waveform. For example, it have been observed that, in some
circumstances, an initial portion of a second signal waveform
(e.g., the first eighth, fifth, third, quarter, half, two thirds,
three quarters, etc.) may be somewhat unstable, while the portion
of the second signal waveform from which data is used in subsequent
calculations is substantially stabilized. While not wishing to be
bound by theory, it is believed that the initial instability of the
second signal waveform observed is caused by minute variations in
the function of fluidics system (e.g., mechanical movement of the
flow control device), membrane effects caused by switching from an
infusion solution to blood (and/or back again, e.g., a
step-change), fluid dynamics (e.g., turbulence) and the like that
may not affect the reliability of the data. Accordingly, in some
embodiments, the system is configured to disregard at least some of
the initial portion of the second signal waveform, when performing
system diagnostics, such as but not limited to evaluating the
system (e.g., system fluidics, system reliability and/or the
like).
[1076] In some embodiments, the processor module is configured to
and/or includes programming that evaluates the sensor system based
at least in part on the second signal by determining a success of a
biological sample draw-back from a host's circulatory system to the
sensor. A success can be determined and/or quantified by a level of
reliability. For example, in some embodiments, the system is
configured to determine that a drawback or infusion was successful
if the reliability is at least 50%. Some embodiments may require a
higher level of reliability to determine that the drawback or
infusion was successful. For example, in some embodiments, the
system is configured to determine that the drawback or infusion was
successful when the reliability is at least 55, 60, 65, 70, 75, 80,
85, 90, or 95% or greater.
[1077] In some further embodiments, the system is configured to
display an analyte value measured during the biological sample
draw-back in response to a determination of a successful biological
sample draw-back. For example, success of a draw-back (e.g., the
level of reliability meets one or more criteria, or the draw-back
is classified as pass) is an indication that the analyte sensor is
sufficiently contacted by the sample such that an accurate
measurement can be made. Thus, the displayed analyte value is not
substantially affected by fluidics problems and can therefore be
considered reliable. In some embodiments, the system is configured
to not display the analyte value measured during the biological
sample draw-back, when the draw-back is determined to be
unsuccessful, such as when the reliability does not meet the one or
more criteria and/or is classified as fail.
[1078] In some embodiments, the processor module is configured to
and/or includes programming that evaluates the sensor system based
at least in part on the second signal by determining a success of
infusing the infusion solution such that a biological sample is
washed from the sensor. As discussed elsewhere herein, the accuracy
of sensor measurement can be affected by the presence of blood
components, from the previously drawn back sample, on the sensor.
For example, in some circumstances, red blood cells from a previous
drawback might affect the current measurement and cause an
inaccurate measurement to be made. In some embodiments, this
problem can be prevented and/or avoided by sufficiently washing the
sensor, such as by reinfusing a drawn-back blood sample and
infusing one or more amounts of infusion solution at one or more
rates, such as according to a flow profile. Thus, in some
embodiments, the system is configured such that the sensor is
washed of the biological sample when the success of the infusion
meets one or more criteria. For example, in some embodiments, the
level of success of infusion is determined and/or quantified by a
level of reliability, such as described above. In other
embodiments, the infusion is classified as successful (e.g., pass)
or not successful (e.g., fail). In some embodiments, the system is
configured to display an analyte value measured in a biological
sample after the infusing the infusion solution in response to a
determination of a successful infusion. Accordingly, if the
infusion was successful, the system displays the analyte value; but
if the infusion was not successful, the system does not display the
analyte value.
[1079] As a non-limiting example, wherein the system is configured
to use a 100 mg/dl glucose reference solution and the plus-enzyme
working electrode is exposed to blood having a glucose
concentration greater than 100 mg/dL, the signal response should
step up. When the plus-GOX working electrode is exposed to blood
having a glucose concentration less than 100 mg/dL, the signal
response should step down. If the system calculated a glucose value
less than 100 mg/dL (e.g. 70 mg/dL) when the plus-GOX working
electrode stepped up, a calibration error is detected and the
system can fail-safe. Similarly, if the system calculated a glucose
value greater than 100 mg/dL (140 mg/dL) when the plus-GOX working
electrode stepped down, an error is detected and the system can
fail-safe.
[1080] Signal Amplitude and/or Noise Amplitude Analysis and
Fail-Safes
[1081] In some embodiments, the system is configured to fail-safe
when analysis of signal amplitude and/or noise amplitude (residual)
of the sensor's working electrode(s) indicates that the integrity
of the system's electrical connections are compromised, such as at
the sensor or at one or more components of the system's
electronics. For example, in the case of a dual-electrode sensor,
an accuracy and/or reliability of the relationship of the
plus-enzyme signal to the non-enzymatic signal is evaluated by
comparing signal amplitudes in calibration solution (or in blood).
For example, the non-enzymatic signal being greater than the
plus-enzyme signal is indicative of a sensor malfunction, and the
system can fail-safe.
[1082] In some embodiments, sensor diagnostics evaluates whether
the calculated sensitivity falls within a predetermined limit
and/or range, for example, 1-10 pA/mg/dL, as described in more
detail elsewhere herein. In some embodiments, the sensor
diagnostics evaluates a difference in signal (raw, filtered and/or
calibrated) between the non-enzymatic working electrode and the
enzymatic working electrode (e.g., in reference/calibration
solution) to determine whether they fall within predetermined
limits and/or ranges. As one example, a sensor/calibration
diagnostic evaluates the baseline of the enzymatic and
non-enzymatic electrodes to determine whether they fall within a
predetermined limit/range.
[1083] In some embodiments, the system is configured to use a
priori information to set tolerances for sensitivity and/or
baseline drift. Preferably, the system is configured to
discriminate between measured changes in sensitivity and/or
baseline from signal artifacts, such as by using tolerance limits
based on historical/empirical data. For example, in some
embodiments, if the sensitivity and/or baseline drifts outside
predetermined limits and the drift is not a transient artifact
(e.g., it persists for a predetermined time period), an error can
be detected in sensor function and/or calibration.
[1084] In yet another alternative embodiment of signal artifacts
detection that utilizes examination or evaluation of the signal
information content, filtered (e.g., smoothed) data is compared to
raw data (e.g., in sensor electronics or in receiver electronics).
In one such embodiment, a signal residual is calculated as the
difference between the filtered data and the raw data. For example,
at one time point (or one time period that is represented by a
single raw value and single filtered value), the filtered data can
be measured at 50,000 counts and the raw data can be measured at
55,500 counts, which would result in a signal residual of 5,500
counts. In some embodiments, a threshold can be set (e.g., 5000
counts) that represents a first level of noise (e.g., signal
artifact) in the data signal, when the residual exceeds that level.
Similarly, a second threshold can be set (e.g., 8,000 counts) that
represents a second level of noise in the data signal. Additional
thresholds and/or noise classifications can be defined as is
appreciated by one skilled in the art. Consequently, signal
filtering, processing, and/or displaying decisions can be executed
based on these conditions (e.g., the predetermined levels of
noise).
[1085] Although the above-described example illustrates one method
for determining a level of noise, or signal artifact(s), based on a
comparison of raw vs. filtered data for a time point (or single
values representative of a time period), a variety of alternative
methods are contemplated. In an alternative exemplary embodiment
for determining noise, signal artifacts are evaluated for noise
episodes lasting a certain period of time. For example, the
processor (in the sensor or receiver) can be configured to look for
a certain number of signal residuals above a predetermined
threshold (representing noise time points or noisy time periods)
for a predetermined period of time (e.g., a few minutes to a few
hours or more).
[1086] In one exemplary embodiment, a processor is configured to
determine a signal residual by subtracting the filtered signal from
the raw signal for a predetermined time period. It is noted that
the filtered signal can be filtered by any known smoothing
algorithm such as described herein, for example a 3-point moving
average-type filter. It is further noted that the raw signal can
include an average value, e.g., wherein the value is integrated
over a predetermined time period (such as 5-minutes). Furthermore,
it is noted that the predetermined time period can be a time point
or representative data for a time period (e.g., 5 minutes). In some
embodiments, wherein a noise episode for a predetermined time
period is being evaluated, a differential can be obtained by
comparing a signal residual with a previous signal residual (e.g.,
a residual at time (t)=0 as compared to a residual at (t)-5
minutes.) Similar to the thresholds described above with regard to
the signal residual, one or more thresholds can be set for the
differentials, whereby one or more differentials above one of the
predetermined differential thresholds defines a particular noise
level. It has been shown in certain circumstances that a
differential measurement as compared to a residual measurement as
described herein, amplifies noise and therefore may be more
sensitive to noise episodes, without increasing false positives due
to fast, but physiological, rates of change. Accordingly, a noise
episode, or noise episode level, can be defined by one or more
points (e.g., residuals or differentials) above a predetermined
threshold, and in some embodiments, for a predetermined period of
time. Similarly, a noise level determination can be reduced or
altered when a different (e.g., reduced) number of points above the
predetermined threshold are calculated in a predetermined period of
time.
[1087] In some embodiments, the amplitude of total signal, which
can also be described as power of the total signal, analyte signal
(with or without baseline (e.g., non-constant noise)), and/or
non-constant noise, is periodically or continuously obtained using
methods such as are described in more detail elsewhere herein
(e.g., RMS method), wherein the amplitude is a measure of the
strength of the signal component. In some embodiments, signal
artifact events are detected by analysis of amplitudes of various
signal components, such as the amplitude of the non-constant noise
component as compared to the amplitude of the analyte signal (with
or without baseline).
[1088] In some embodiments, a start of a signal artifact event is
determined when the amplitude (power) of a signal artifact meets a
first predetermined condition. In one embodiment, the first
predetermined condition includes a residual amplitude of at least
about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or 25% of the
total signal or analyte signal amplitude (with or without
baseline). In another embodiment, the first predetermined condition
includes a differential amplitude (amplitude of a differential) of
at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or
25% of the total signal or analyte signal amplitude (with or
without baseline). In some embodiments, the first predetermined
condition includes a plurality of points (e.g., non-constant noise
signal, residual, or differential) within a predetermined period
(e.g., 5, 10, 30, or 60 minutes) above a predetermined threshold
(e.g., an amplitude or a percentage amplitude), wherein the
plurality of points includes 2, 3, 4, 5, 6, 7, 8 or more
values.
[1089] In some embodiments, an end of a signal artifact event is
determined when then the amplitude (power) of a signal artifact
meets a second predetermined condition. In one embodiment, the
second predetermined condition includes a residual amplitude of no
more than about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or
25% of the total signal or analyte signal amplitude (with or
without baseline). In another embodiment, the second predetermined
condition includes a differential amplitude of no more than about
2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or 25% of the total
signal or analyte signal amplitude (with or without baseline). In
some embodiments, the second predetermined condition includes a
plurality of points (e.g., non-constant noise signal, residual, or
differential) within a predetermined period (e.g., 5, 10, 30, or 60
minutes) below a predetermined threshold (e.g., an amplitude or a
percentage amplitude), wherein the plurality of points includes 2,
3, 4, 5, 6, 7, 8 or more values. Additional description can be
found in US Patent Publication Nos. US-2005-0043598-A1,
US-2007-0032706-A1, US-2007-0016381-A1, and US-2007-0033254-A1,
each of which is incorporated by reference herein in its
entirety.
[1090] Auto-Calibration
[1091] Some preferred embodiments are configured for
auto-calibration of the sensor system, wherein "auto-calibration"
includes the use of one or more internal references to calibrate
the sensor system. In some embodiments, auto-calibration includes
systems and methods configured to calibrate the sensor based solely
on internal reference values. For example, the system can be
configured to obtain internal reference values by exposing the
sensor to one, two or more calibration/reference solution, as
described elsewhere herein. As another example, the sensor can be
configured with a reference sensor disposed adjacent to the
continuous analyte sensor, wherein both the continuous analyte and
reference sensors obtain internal reference values for a
substantially constant reference analyte (e.g., O.sub.2), which are
then used to calibrate the continuous analyte sensor (see the
sections entitled "Optical Detection" and "Calibration Systems and
Methods of Calibrating Dual-Electrode Sensors" above). However, in
some alternative embodiments of auto-calibration, one or more
external reference values can be used to complement and/or confirm
calibration of the sensor system.
[1092] In some preferred embodiments, the system is configured to
intermittently expose the sensor to a biological sample; however
configurations of the sensor system that allow continuous exposure
of the sensor to the biological sample are contemplated. In some
embodiments, the system is configured to intermittently or
periodically expose the sensor to a reference, however
configurations of the sensor system that allow one or more
independent or non-regular reference measurements initiated by the
sensor system and/or a user are contemplated. In the exemplary
embodiment of a sensor system such as described with reference to
FIGS. 8A to 8C, the system is configured to cycle between a
measurement phase and calibration phase (with optional other phases
interlaced therein (e.g., flush and KVO)).
[1093] In general, timing of auto-calibration can be driven by a
variety of parameters: preset intervals (e.g., clock driven) and/or
triggered by events (such as detection of a biological sample at a
sensor). In some embodiments, one or more of the phases are purely
clock driven, for example by a system configured to control the
timing housed within a flow control device, remote analyzer, and/or
other computer system. In some embodiments, one or more of the
phases are driven by one or more events, including: exposure of the
sensor to a biological sample (e.g., blood) exposure of sensor to a
reference (e.g., calibration solution), completion of calibration
measurement, completion of analyte measurement, stability of signal
measurement, sensor for detecting a biological sample, and the
like.
[1094] In one exemplary embodiment, calibration and measurement
phases are driven by cleaning of sensor; namely, systems and
methods are configured to detect when the sensor is in the
biological sample and/or in the reference solution (e.g.,
calibration solution), wherein the system is configured to switch
to appropriate phase responsive to detection of that
sample/solution.
[1095] In another exemplary embodiment, an AC signal is placed on
top of a DC signal (e.g., in an amperometric electrochemical
analyte sensor), wherein systems and methods are configured to
analyze an impedance response to the AC signal and detect a
biological sample thereby.
[1096] In yet another exemplary embodiment, systems and methods are
configured for analyzing the sensor's signal, wherein a change from
a known reference solution (e.g., a known analyte concentration)
can be detected on the signal, and the switch from the calibration
phase to the measurement phase occur responsive thereto; similarly,
the system can be configured to switch back to the calibration
phase responsive to detection of the known signal value associated
with the reference solution.
[1097] In yet another exemplary embodiment, systems and methods are
configured to switch between phases responsive to one or more
sensors configured to detect the biological sample and/or reference
solution at a particular location.
[1098] In some embodiments, the sensor system is partially or fully
controlled by a clock (e.g., predetermined time intervals), which
timing can be confirmed by any of the events (e.g., triggers or
sensors) described above.
[1099] In one exemplary embodiment, systems and methods are
provided to enable auto-calibration of an integrated glucose sensor
system with minimal user interaction. In this exemplary embodiment,
the integrated sensor system is provided with the components
described above, including a fluids bag, a flow control device, IV
tubing, a flow control device, a remote analyzer, a local analyzer
and a sensor/catheter, for example. At system start-up, a health
care worker inserts the catheter and sensor into a host and injects
a first reference solution (e.g., zero glucose saline solution)
into the IV tubing, wherein the system is configured to allow a
predetermined time period (e.g., 20 minutes) for the first
reference solution to pass through the IV tubing and into the
catheter. Subsequently, the health care worker couples the fluids
bag to the IV tubing, wherein the fluids bag includes a second
reference solution (e.g., 100 mg/dl glucose solution) configured to
follow the first reference solution in the IV line. After injecting
the first reference solution and coupling the second reference
solution, the health care worker initiates the integrated sensor
system (e.g., through the remote analyzer touch screen) after which
the integrated sensor system automatically calibrates and functions
for 24 hours without necessary user interface (for system
calibration and/or initiation). In some embodiments, the sensor
system is re-calibrated every 24 hours by injection of a new first
reference solution (e.g., zero glucose saline solution).
[1100] In the above-described exemplary embodiment, the system is
configured to calibrate the sensor with the first and second
reference solution and using the methods described in the section
entitled, "Systems and Methods for Processing Sensor Data."
Additionally, the system is configured to automatically detect the
difference in signal associated with the first and second reference
solutions, for example, through steady state detection of a
difference in signal level.
[1101] Methods of Integrated System Set-Up and Initial Use In
Vivo
[1102] Referring to FIG. 6, in one exemplary embodiment, the
present system is configured and arranged for continuous analyte
detection in the circulatory system of a host, such as a human, and
for fluid infusion. As a non-limiting example, in some embodiments,
the continuous analyte sensor is a glucose sensor at least
partially disposed in a fluid coupler. In this embodiment, system
600 set-up and installation includes implanting a catheter into one
of the host's peripheral veins, fluidly coupling the sensor (e.g.,
including fluid coupler) to the implanted catheter, fluidly
coupling the IV tubing and infusion solution 602a to the fluid
coupler operatively connected to the sensor, to a controller and/or
display (604 and/or 610), installation of the tubing into the flow
control device 604, and initializing the system (e.g., turning on
the flow control device). In some circumstances, an operator (e.g.,
a nurse, doctor or other medical caretaker) prepares a calibration
solution by injecting an amount of glucose into an IV bag of
infusion solution, such as but not limited to a saline hydration
solution, and mixing the contents of the bag. In other
circumstances, a commercially prepared calibration solution is
used. In some circumstances, a medicament, nutrient or other
substance may be added to the infusion solution. The bag of
prepared infusion solution 602a is suspended on an IV stand 612,
such as a stand that also supports the flow control device 604.
[1103] Referring to FIG. 1F, the operator implants a catheter 12 in
one of the host's peripheral veins, such as a vein located in the
host's forearm, using standard hospital protocol. Next, the
operator grasps the fluid coupler 20, inserts analyte sensor 14
into the catheter's lumen and fluidly couples the first end 20a of
the fluid coupler to the catheter's hub 18. Note that the sensor is
protected by the slotted sheath 26 during insertion.
Advantageously, in some embodiments, the fluid coupler and the
slotted sheath are configured and arranged such that the slotted
sheath prevents blood from coming out of the fluid coupler's second
end, until the slotted sheath is removed (e.g., just prior to
connection of the second end 20b to the IV tubing). In alternative
embodiments, such as that shown in FIGS. 1F-1J, the analyte sensor
is located within the fluid coupler's lumen and the second end
includes a cap configured and arranged to prevent blood coming out
of the second end prior to connection of the IV tubing. In some
embodiments, the operator (e.g., user) sets up the flow control
device, then implants the catheter and sensor and then connects the
tubing to the fluid coupler. In other embodiments, the catheter and
sensor are implanted prior to set-up of the flow control device
with subsequent connection of the IV tubing to the fluid coupler.
Either sequence of events is acceptable, as well as a matter of
personal preference and/or hospital protocol.
[1104] In preferred embodiments, the IV tubing 606 is configured
and arranged for installation into a flow control device 604. In
some embodiments, the flow control device and tubing are configured
and arranged such as is shown in FIGS. 10A-10D. However, other flow
control device and/or tubing configurations are used, in some
embodiments. In some embodiment, the flow control device is
configured to be moved (e.g., by hand or in response to pressing a
button) to the gravity flow valve position (e.g., see FIG. 10C), if
it is not already in that position, such that the groove 803 is not
blocked by the roller 802. In preferred embodiments, the valve is
configured to automatically move to the gravity flow valve position
at shut-off and/or termination of a sensor session. In other
embodiments, the system is configured such that the valve moves to
the gravity flow position when the system is turned on.
[1105] In preferred embodiment, the operator fluidly couples the
tubing assembly 606a to the fluid reservoir and/or the fluid
coupler. In some embodiments, additional lengths of IV tubing 606
are used to make these fluid connections, as is known in the art.
To install the tubing assembly 606a, the operator grasp by the
connector ends 606c, 606d and stretches the tubing therebetween.
The operator orients the stretched tubing assembly such that its
central portion 606b aligns with the valve's channel 803 and the
tubing's male interconnector (e.g., connector 606d) aligns with the
valve's female interconnector 809. The operator then inserts the
tubing assembly into the valve channel and releases the connectors,
such that the tubing assembly's central portion relaxes to a less
stretched (but still stretched and linear) configuration. The
operator connects the tubing assembly (e.g., via an optional length
of IV tubing) to the IV solution. Then, the operator removes the
protective sheath from the sensor by pulling it out of the fluid
coupler by its hub 28 and connects the tubing assembly to the fluid
coupler's second end (e.g., via an optional length of IV
tubing).
[1106] In preferred embodiments, the system is configured such that
the operator initiates system start-up after installing the sensor,
the tubing, and the like, such as described above. In some
embodiments, system initiation and/or start-up include, but are not
limited to, turning the system on, selecting a flow profile,
entering system configuration information (e.g., type of sensor,
type of catheter, type of infusion solution), entering user
information (e.g., patient ID, patient type, patient target analyte
levels, etc.). In some embodiments, the system is configured to be
initiated when the user presses a button, flips a switch and/or
selects (e.g., a start-up protocol) from a menu on the user
interface. In some embodiments, the system is configured to
automatically receive and/or recognize at least some of the
start-up information, such as via a identification information, a
code and/or key in the interconnection of the tubing assembly and
the flow control device, via an RFID chip in the patient arm band,
via optically scanning a bar code on the patient's chart/arm band
and/or on the fluid coupler and/or catheter, and the like. In some
embodiments, the flow control device system electronics are
configured for operator selection of a flow profile from a menu of
flow profiles (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more flow
profiles). In preferred embodiments, the system is configured for
selection of a flow profile (by the operator) at least during
system start-up/initiation. However, in some further embodiments,
the system electronics are configured for selection of another
profile and/or modification (e.g., re-programming) of the flow
profile during system use. For example, if during use of the
system, infusion solution is changed from a first type to a second
type (e.g., from saline to a glucose solution), the flow profile
can be modified to accommodate that infusion solution change.
[1107] In some embodiments, the system is configured to begin
intermittently infusing the calibration solution and drawing back
samples of the host's blood (e.g., according to the flow profile),
energizing the sensor and generating measurements of the
calibration solution and blood, and the like, upon system
initiation/start-up by the operator. For example, depending upon
the flow profile specifications, the flow control device
alternately infuses (e.g., at one or more rates) the calibration
solution for about 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0 or
more minutes, then draws back a blood sample, returns the sample to
the host (e.g., reinfuse the sample), and then returns to infusing
the calibration solution. Calibration measurements are taken during
infusion phases of the flow profile. Blood analyte measurements are
taken during draw-back phases of the flow profile (e.g., when the
sensor is bathed in a blood sample). In some embodiments, the
sensor is a dual-electrode glucose sensor, and the system is
configured to collect signal(s) from both the plus-enzyme (e.g.,
plus GOX) and no-enzyme working electrodes.
[1108] In some embodiments, the system is configured to follow a
"break-in" procedure (also referred to as "run-in"). For example,
in some embodiments, the system is configured to cycle between
infusion and sample draw-back for about 0.1, 0.2, 0.3, 0.4, 0.5,
0.75, 1.0, 1.25, 1.5, 1.75 or 2-hours. In one embodiments, at about
1-hour, the processor module is configured to and/or includes
programming that evaluates sensor stability (e.g., sensor
break-in), such as by evaluating the rates of change of the
no-enzyme waveform, the amplitude of the no-enzyme signal, and/or
the like. In some embodiments, the system is configured to prompt
the operator for input of a reference blood glucose value. For
example, in one embodiment, the system is configured to wait about
1-hour to about 1.25-hours before prompting the operator for a
reference analyte value. A reference analyte value can be obtained
using any method known in the art. For example, in the case of a
continuous glucose sensor, the operator can use a hand-held glucose
meter to measure the host's blood glucose, and enter the measured
value into the system via the user interface. In some embodiments,
the processor module uses one or more entered reference values to
calibrate the sensor using substantially time-corresponding sensor
measurements. In some embodiments, the system is configured to
utilize an entered reference value as a b.sub.offset.
[1109] In some embodiments, the system is configured to display the
host's blood glucose concentration in response to the processor
module determining that break-in is complete and/or after sensor
calibration. For example, if the processor module determines that
the sensor signal has substantially stabilized, the system displays
analyte values to the operator. If, on the other hand, the
processor module determines that the sensor signal is not yet
substantially stabilized, then the system does not display an
analyte value to the operator. In some circumstances, the system is
configured to prompt the operator to input additional reference
analyte values. For example, in one embodiment, the system is
configured to wait a period of time (e.g., 5, 10, 15, 20, 30, 40,
50 or 60 minutes) and then to request a reference analyte value. In
a further embodiment, if the sensor signal has still not
stabilized, then the system is configured to wait another period of
time (e.g., 5, 10, 15, 20, 30, 40, 50 or 60 minutes) and then to
request a reference analyte value. In another further embodiment,
if the sensor signal has not substantially stabilized after a
programmed period of time (e.g., 1.25, 1.5, 1.75, 2, 2.5, or
3-hours), then the system is configured to declare a sensor failure
and to prompt the user to install a new sensor.
[1110] In preferred embodiments, the flow control device is
configured to infuse the calibrant and draw-back samples according
to the flow profile selected by the operator. In preferred
embodiments, the sensor is configured and arranged to generate
sensor data, and the processor module is configured to and/or
includes programming that processes the sensor data (e.g., as
described elsewhere herein), such that the analyte concentration of
the host's blood is measured in real-time and/or displayed on a
user interface. In preferred embodiments, the processor module is
configured to and/or includes programming that intermittently
calibrates (e.g., re-calibrates) the sensor.
EXAMPLES
Example 1: Glucose Sensor System Trial in Dogs
[1111] Referring now to FIG. 4, glucose sensor systems of the
embodiment shown in FIG. 1 were tested in dogs. The glucose sensors
were built according to the preferred embodiments described herein.
Namely, a first sensor (Test 1) was built by providing a platinum
wire, vapor-depositing the platinum with Parylene to form an
insulating coating, helically winding a silver wire around the
insulated platinum wire (to form a "twisted pair"), masking
sections of the electroactive surface of the silver wire,
vapor-depositing Parylene on the twisted pair, chloridizing the
silver electrode to form a silver chloride reference electrode, and
removing a radial window on the insulated platinum wire to expose a
circumferential electroactive working electrode surface area
thereon, this assembly also referred to as a "parylene-coated
twisted pair assembly."
[1112] An electrode domain was formed over the electroactive
surface areas of the working and reference electrodes by dip
coating the assembly in an electrode solution and drying. An enzyme
domain was formed over the electrode domain by subsequently dip
coating the assembly in an enzyme solution and drying. A resistance
domain was formed over the enzyme domain by spraying the resistance
domain solution on the sensor construct.
[1113] After the sensor was constructed, it was placed in the
protective sheath and then threaded through and attached to the
fluid coupler.
[1114] A second sensor (Test 2) was constructed in the same manner
as the first, except that the silver wire was disposed within
(e.g., coiled within) the fluid coupler. Accordingly, only the
platinum working electrode (a single wire) was inserted into the
catheter during the experiment.
[1115] Prior to use, the sensors were sterilized using electron
beam.
[1116] The forelimb of an anesthetized dog (2 years old, .about.40
pounds) was cut down to the femoral artery and vein. An
arterio-venous shunt was placed from the femoral artery to the
femoral vein using 14 gauge catheters and 1/8-inch IV tubing. A
pressurized arterial fluid line was connected to the sensor systems
at all times. The test sensor systems (test 1 and test 2) included
a 20 gauge.times.1.25-inch catheter and took measurements every 30
seconds. The catheter was aseptically inserted into the shunt,
followed by insertion of the sensor into the catheter. A
transcutaneous glucose sensor (control) of the type disclosed in
U.S. Patent Publication No. US-2006-0155180-A1 was built and placed
in the dog's abdomen according to recommended procedures. The dog
was challenged with continuous incremental IV infusion of a 10%
dextrose solution ("glucose challenge") until the blood glucose
concentration reached about 400 mg/dL.
[1117] FIG. 4 shows the experimental results. The thick line
represents data collected from the Test 1 sensor. The thin line
represents data collected from the Test 2 sensor. Diamonds
represent data collected from a hand-held blood glucose meter
(SMBG) sampled from the dog's abdomen. Raw glucose test data
(counts) are shown on the left-hand Y-axle, glucose concentrations
for the "SMBG" controls are shown on the right-hand y-axle, and
time is shown on the X-axle. Each time interval on the X-axle
represents 29-minutes (e.g., 10:04 to 10:33 equals 29 minutes).
Immediately upon insertion into a catheter, each test sensor began
collecting data with substantially no sensor equilibration time
(e.g., break-in time). Each test sensor responded to the glucose
challenge substantially similarly to the control sensor. For
example, each device shows the glucose signal increasing from about
3200 counts at 10:33 to about 6000-6700 counts at 11:31. Then, each
device showed a rapid decrease in glucose signal, to about 4700
counts at 12:00. Additionally, the response of the test sensors and
the control sensor were substantially similar (e.g., the majority
of the test data was substantially equivalent to the SMBG data at
each time point). From these experimental show that an indwelling
glucose sensor system (as described herein) in contact with the
circulatory system can provide substantially continuous glucose
monitoring in a clinical setting.
Example 2: Glucose Sensor System Trial in Pigs
[1118] Referring now to FIG. 5, four glucose sensor systems of the
embodiment shown in FIG. 1 were tested in a pig (.about.104 lb),
using the protocol described for Example 1, above. Glucose was
continuously infused at increasing rates through a distally placed
IV catheter until a readout of 300-400 mg/dl blood glucose was
achieved (total 300 ml of a 10% dextrose IV solution). FIG. 5 shows
the experimental results. Lines indicated the data from the four
sensors (Test 1 through Test 4). Diamonds represent control
measurements made with a hand-held glucose meter (SMBG). Raw
glucose test data (counts) are shown on the left-hand Y-axle,
glucose concentrations for the "SMBG" controls are shown on the
right-hand y-axle, and time is shown on the X-axle. Test results
show that though the sensors varied in sensitivity, each test
sensor responded to glucose challenge substantially similarly to
the control sensor (SMBG). These experimental results show that an
indwelling glucose sensor system (of the preferred embodiments) in
contact with the circulatory system can substantially continuously
track glucose in a clinical setting.
Example 3: Glucose Sensor System with Flow Control Device Trial in
Pigs
[1119] Referring now to FIG. 17, a glucose sensor was built
according to the preferred embodiments described herein. Namely, a
test sensor was built by providing a platinum wire,
vapor-depositing the platinum with Parylene to form an insulating
coating, helically winding a silver wire around the insulated
platinum wire (to form a "twisted pair"), masking sections of the
electroactive surface of the silver wire, vapor-depositing Parylene
on the twisted pair, chloridizing the silver electrode to form a
silver chloride reference electrode, and removing a radial window
on the insulated platinum wire to expose a circumferential
electroactive working electrode surface area thereon, this assembly
also referred to as a "parylene-coated twisted pair assembly."
[1120] An electrode domain was formed over the electroactive
surface areas of the working and reference electrodes by dip
coating the assembly in an electrode solution and drying. An
interference domain was formed over the electrode domain by
subsequently dip coating the assembly in an interference domain
solution and drying. An enzyme domain was formed over the
interference domain by subsequently dip coating the assembly in an
enzyme solution and drying. A resistance domain was formed over the
enzyme domain by spraying the resistance domain solution on the
sensor construct.
[1121] The test sensor was then located within a 20 gauge catheter
and inserted in the femoral vein of a non-diabetic pig. The
catheter was connected to an integrated sensor system 600 of the
preferred embodiments. The flow control device 604 (e.g., a roller
valve as depicted in FIGS. 8A-8C) was configured to move between
steps one and two, as described in the section entitled "Flow
Control Device Function," above. A 107-mg/dL glucose solution was
used to calibrate the sensors (e.g., flows from the reservoir 602,
through the tubing 606, to the catheter 12). To mimic a diabetic's
hyperglycemic state, a gradual infusion of 26% dextrose was given,
until the pig's blood glucose was about 600 mg/dl. Then to mimic a
hypoglycemic state, 10 U Humulin N was given, until the pig's blood
glucose was about 50 mg/dl. Then, the pig's blood glucose was
raised to about 100 mg/dl by a second 26% dextrose infusion.
[1122] FIG. 17 is a graphical representation showing uncalibrated
glucose sensor data and corresponding blood glucose values over
time in a pig. Raw counts are represented on the left Y-axis.
Glucose concentration is shown on the right Y-axis. Time is shown
on the X-axis. Test measurements (e.g., measurements of blood
glucose concentration obtained with the test sensor, raw counts)
are shown as small, black dots. Control measurements (e.g., jugular
vein blood samples analyzed on a Yellow Springs Instrument (YSI)
glucose analyzer) are shown as diamonds.
[1123] During the experiment, the system was configured to
alternate between calibration measurements (with the 107 mg/dl
glucose solution) and blood glucose measurements, as described in
the sections entitled "Step one: Contacting Sensor with Calibration
Solution and Calibration" and "Step Two: Sample Collection and
Measurement," respectively. Accordingly, as the experiment
proceeded the test signal oscillated between calibration solution
(107 mg/dl) and blood glucose measurements. The sensor (test) blood
glucose measurement correlated tightly with the control blood
glucose measurements. For example, as the pig's blood glucose
concentration increased (due to infusion of glucose), so did the
test measurements, reaching about 550 mg/dl at about 12:20.
Similarly, as the pig's blood glucose concentration decreased (due
to infusion of insulin), so did the test measurements, decreasing
to about 50 mg/dl at about 14:45.
[1124] From these data, it was concluded that a glucose sensor
system of the preferred embodiments (including a valve as described
with reference to FIGS. 8A to 8C) accurately and sensitively
measures intravenous glucose concentration over a wide dynamic
range.
Example 4: Glucose Sensor System with Flow Control Device Trial in
Humans
[1125] Referring now to FIG. 18, a glucose sensor, constructed as
described in Example 3, and an integrated sensor system (as
described in Example 3) were tested in a volunteer, diabetic host.
The flow control device was configured as shown in FIGS. 8A-8C. The
system was configured to alternate between a calibration phase and
a blood glucose measurement phase, as described elsewhere herein.
At sensor/catheter initialization, a 0 mg/dl glucose saline
solution filled syringe was injected into the IV tubing and the
fluids bag including 100 mg/dl glucose heparinized saline solution
was subsequently coupled to the tubing. The system was then turned
on (e.g., sensor initialized). The 0 mg/dl glucose saline solution
passed over the sensor, after which the 100 mg/dl glucose
heparinized saline solution subsequently passed over the sensor
allowing for initial calibration information to be collected. The
system, including a flow control device as described with reference
to FIGS. 8A to 8C, then oscillated between exposure of the sensor
to a blood sample and exposure of the sensor to the 100 mg/dl
glucose heparinized saline solution. The sensor auto-calibrated by
a combination of calibration information obtained from measurement
of the 0 mg/dl-glucose and 100 mg/dl-glucose saline solutions and
the step-change-response of the sensor to the blood sample,
according to the methods described in the section entitled "Systems
and methods for Processing Sensor Data." No external measurements
(e.g., blood glucose measurements by YSI or finger stick) were used
to calibrate the system in this example. During the experiment, the
flow control device cycled between step one (measuring the 100
mg/dl-glucose solution) and step two (blood sample take up and
measuring the blood glucose concentration), such that one cycle was
completed every 5-minutes. The experiment was conducted for a
period of about 2.5 days. The host followed her usual schedule of
meals and insulin injections.
[1126] FIG. 18 is a graphical representation showing calibrated
venous blood glucose sensor measurements (test, black dots) and
corresponding control blood glucose measurements (YSI, large
circles) over time in the volunteer diabetic host. Glucose
concentration is shown on the Y-axis and time on the X-axis. Test
measurements tracked closely with control measurements, ranging
from about 350 mg/dl, at about 10:00 and about 15:30, to about 50
mg/dl, at about 11:45. From these data, it has been concluded that
1) the sensor calibration methods of the preferred embodiments
accurately calibrate the sensor and 2) the glucose sensor system of
the preferred embodiments accurately measures intravenous glucose
concentration over a wide dynamic range, for two or more days, in
humans.
Example 5: Detection of Crosstalk In Vitro
[1127] In general, crosstalk in dual-electrode sensors can be
examined by recording the signal detected at each working electrode
while placing them in a series of analyte solutions. This example
describes one exemplary in vitro test for crosstalk on a
dual-electrode analyte sensor. A variety of dual-electrode analyte
sensors can be tested for crosstalk, using this method.
[1128] First, the sensor to be tested is placed in a phosphate
buffered saline (PBS) for several minutes, such as until a stable
signal is detected from both working electrodes. Next, the sensor
is challenged with glucose solutions and optionally with one or
more known noise-causing substances. For example, sensor can be
placed sequentially in a series of glucose solutions (e.g.,
40-mg/dl, 200-mg/dl and 400-mg/dl glucose in PBS) and the signals
from the two working electrodes graphed.
[1129] If there is no crosstalk between the working electrodes,
then, as the sensor is placed in solutions of increasingly higher
glucose concentration, the graphed signal of the Plus GOx electrode
should show corresponding signal increases, while the No GOx
electrode signal should exhibit little or no change in signal.
However, when the sensor is placed in a solution of a known
noise-causing species (e.g., acetaminophen, ibuprofen, vitamin C,
urea, and the like), both working electrodes (Plus GOx and No GOx)
should exhibit an increase in signal. In some circumstances, this
increase in signal is a dramatic spike in signal.
[1130] If there is crosstalk, then the signals from both electrodes
should increase as the sensor is moved to solutions of increased
glucose concentration. Similarly, when the sensor is placed in a
solution of a known noise-causing species, both working electrodes
should exhibit an increase in signal.
Example 6: Effect of Electroactive Surface Size in Dual-Electrodes
In Vivo
[1131] The effect of size of the electroactive surfaces (of the
working electrodes) on noise measurement was examined in
non-diabetic human hosts. Sensors having electroactive surfaces of
different sizes, and lacking GOx in the enzyme layer were
constructed as follows. Clean, insulated Pt/Ir wires were separated
into two groups. For Group 1, 0.029'' of the insulation was removed
from each wire (e.g., about its entire circumference), to expose
electroactive surfaces. For Group 2, the same procedure was
performed, except that two sequential 0.029'' portions of the
insulation were removed; effectively doubling the size of the Group
2 electroactive surfaces relative to those of Group 1. After
exposure of the electroactive surfaces, the two groups of wires
were treated identically. On each wire, a portion of the sensor's
membrane was fabricated by the sequential application (and curing
thereof) of electrode domain, enzyme domain and resistance domain
materials. The enzyme domain material contained no active GOx, so
that the sensors would be able to detect only noise (no analyte).
Next, pairs of wires (e.g., two Group 1 wires or two Group 2 wires)
were aligned such that the electroactive surfaces were parallel to
each other, and then twisted together. An Ag/AgCl ribbon was
wrapped around a portion of the twisted wires (to form the
reference electrode), and then additional resistance domain
material was applied to the assembly. Each host consumed 1,000-mg
of acetaminophen near the end of the trial, so that the affect of a
known interferent could be examined.
[1132] FIG. 19A is a graph illustrating the in vivo experimental
results from implantation of a Group 1 sensor (one 0.029''
electroactive surface area per electrode). The Y-axis represents
raw counts and the X-axis represents time. The data collected from
each electroactive surface is shown as a line (E1, No GOx and E2,
No GOx). Please note that the data represents only the noise
component of the signal. No analyte component was detected, due to
the lack of GOx in the portions of the membrane adjacent to the
electroactive surfaces. Referring now to FIG. 19A, the noise signal
detected by each of the working electrodes (E1, E2) fluctuated
widely throughout the implantation time. The amplitude of the noise
component detected by E2 was substantially greater than the noise
component detected by E1. For example, referring to the data
circled by oval A, the noise signal peaks detected by E2 were
substantially greater than those detected by E1. Additionally, the
noise fluctuations between the two working electrodes were not
always in the same direction. For example, referring to the data
circled by oval B, the E2 noise signal component increased while
the E1 noise signal component decreased. When the sensor was
challenged with acetaminophen (drug consumption indicated by the
arrow), both electrodes registered a substantial increase in noise
signal, wherein the shapes of the curves were substantially
similar. However, E1 detected a substantially lower total amount of
noise when compared with that detected by E2; this difference in
signal amplitude (in response to a non-biologic interferent)
indicates that the signals (e.g., on the two working electrodes)
did not have substantially similar sensitivities.
[1133] FIG. 19B is a graph illustrating the in vivo experimental
results from implantation of a Group 2 sensor (two 0.029''
electroactive surface areas per electrode). As described above, the
Group 2 electroactive surfaces are about two-times as large as
those of the Group 1 sensors. As before, the Y-axis represents raw
counts and the X-axis represents time, and the data collected from
each electroactive surface is shown as a line (E1, No GOx and E2,
No GOx). As before, the data represents only the noise component of
the signal. No analyte component was detected, due to the lack of
GOx in the portions of the membrane adjacent to the electroactive
surfaces. Referring now to FIG. 19B, the noise signal detected by
each of the working electrodes (E1, E2). Throughout the course of
the experiment (.about.20-hours), noise signals detected by E1 and
E2 tracked very closely throughout the entire experiment. Namely,
the noise signals detected by E1 and E2 were of substantially the
same amplitude and followed substantially similar fluctuations,
varying from about 7,000 counts (at 4:00 PM) to about 4500 counts
(from about 6:30 AM to about 9:00 AM). Even when the Group 2 sensor
was challenged with acetaminophen (a known non-biological
interferent that should cause a false signal on the sensor), the
working electrodes recorded substantially equal signal amplitudes
(6,900 counts) and followed substantially similar wave forms having
substantially equivalent amplitudes; these data indicate that the
two working electrodes had substantially equal sensitivities.
[1134] From these data, the inventors concluded that the
electroactive surfaces of a dual-electrode glucose sensor must be
sufficiently large in order for the two electrodes to detect
substantially equal noise signal components. For example, in this
experiment, the electroactive surfaces of the Group 1 working
electrodes, which did not measure noise equivalently, were 0.029''
(e.g., along the electrode's length); while electroactive surfaces
of the Group 2 working electrodes, which did measure noise
substantially equivalently, were two times as large (e.g.,
2.times.0.029''=0.058'' along the electrode's length) as those of
the Group 1 working electrodes.
Example 7: Effect of Electroactive Surface Spacing in
Dual-Electrodes In Vivo
[1135] The effect of the spacing of the electroactive surfaces (of
the working electrodes) on noise measurement was examined in
non-diabetic human hosts. Sensors having two different
configurations were built and tested. Sensors of Configuration 1
(Config. 1) included Plus GOx and No GOx working electrodes with
non-aligned (e.g., miss-aligned, skewed) electroactive surfaces. In
other words, the electroactive surfaces were spaced such that, in
the completed sensor, one electroactive surface would be more
proximal to the sensor's tip than then other. Sensors of
Configuration 2 (Config. 2) also included Plus GOx and No GOx
working electrodes, except that the electroactive surfaces were
closely aligned (e.g., parallel). In Config. 2, the membrane was
the insulator between the two working electrodes, enabling the very
close spacing (i.e., the thickness of the membrane determined the
spacing between the two working electrodes, between about 0.001
inches to about 0.003 inches between the two working
electrodes.)
[1136] Config. 1 sensors were fabricated as follow. For each
sensor, two clean, insulated Pt/Ir wires were wound together (and
an Ag/AgCl ribbon twisted there around), followed by removal of a
portion of the insulating material from each wire to create the
electroactive surfaces. The electroactive surfaces were offset
(e.g., not next to each other) relative to the sensor's tip. The
twisted wire pairs were then dipped in enzyme domain solution
(including GOx) just far enough such that only the electroactive
surface closest to the tip of the sensor was coated with the enzyme
domain material (e.g., E1, Plus GOx). The electroactive surface
farthest from the sensor tip was not coated with the enzyme domain
material (e.g., E2, No GOx). After curing, resistance domain
material was applied to the twisted pairs of wires.
[1137] Config. 2 sensors were fabricated as follow. Clean,
insulated Pt/Ir wires were divided into two groups. Electrode and
enzyme (Plus GOx) domain materials were sequentially applied to the
E1, Plus GOx working electrode wires. Electrode and enzyme (No GOx)
domain materials were sequentially applied to the E2, No GOx
working electrode wires. Resistance domain material was applied to
all wires individually (e.g., to form independent/discontinuous
first and second resistance domains). After the resistance domain
material was cured, one each of the E1, Plus GOx and E2, No GOx
were placed together such that the wires' electroactive surfaces
were aligned, and then twisted together to form a twisted pair. An
Ag/AgCl ribbon was wrapped around each twisted pair (but not
covering the electroactive surfaces), followed by application of a
continuous resistance domain (e.g., a third resistance domain) over
the sensor. The resulting sensors included a coaxial helix
configuration similar to that shown in FIG. 18 of U.S. Patent
Publication No. US-2008-0083617-A1, incorporated herein by
reference in its entirety.
[1138] FIG. 20A is a graph illustrating the in vivo experimental
results from implantation of a Config. 1 sensor (non-aligned
electroactive surfaces). The Y-axis represents raw counts and the
X-axis represents time. The E1, Plus GOx electrode detected both
glucose and noise signal components while the E2, No GOx electrode
detected only the noise signal component. Throughout most of the
experiment's duration, the two working electrodes recorded signals
having somewhat similar waveforms with the two lines being
relatively flat with little fluctuation in amplitude (the volunteer
was not diabetic, and thus would generally not have large
fluctuations in glucose level). During the acetaminophen challenge,
the E1, Plus GOx signal rapidly peaked at about 12,000 counts and
then gradually declined, while the E2, No GOx signal peak was much
lower in amplitude (6,000 counts).
[1139] FIG. 20B is a graph illustrating the in vivo experimental
results from implantation of a Config. 2 sensor (aligned
electroactive surfaces). The Y-axis represents raw counts and the
X-axis represents time. In general, the E1, Plus GOx electrode
detected both glucose and noise signal components while the E2, No
GOx electrode detected only the noise signal component. Throughout
most of the experiment's duration, the two electrodes recorded
signals having substantially similar waveforms; though the E1, Plus
GOx electrode signal was generally higher in amplitude than that of
the E2, No GOx electrode. When the sensor was challenged with
acetaminophen, the signals of both working electrodes rapidly
peaked at about 11,000-12,000 counts (e.g., the amplitudes of the
two peaks were substantially equivalent/similar) and then gradually
declined.
[1140] From these data, the inventors concluded that the
electroactive surfaces of a dual-electrode glucose sensor must be
sufficiently close together in order for the two electrodes to
detect substantially equivalent noise signal components.
Additionally, the inventors concluded that for a dual-electrode
sensor including the combination of a continuous resistance domain
disposed over discontinuous resistance domains (e.g., applied
independently to the two working electrodes) the detected signal
amplitudes more closely correspond to each other. This improves
mathematical noise correction by enabling better noise signal
subtraction.
Example 8: Use of Dual-Electrode Glucose Sensors in Intravenous
Porcine Model
[1141] Six dual-electrode glucose sensor IV systems, including a
dual-electrode glucose sensor (e.g., including a first working
electrode E1 (e.g., configured to generate signals associated with
both glucose and non-glucose-related species having
oxidation/reduction potentials that overlap with that of glucose)
and a second working electrode E2 (e.g., configured to generate
signals associated with non-glucose-related species having
oxidation/reduction potentials that overlap with that of glucose))
and a fluid control system (including a catheter inserted into a
peripheral vein) were tested in a porcine model, as described
elsewhere herein. A 100-mg/dl-glucose solution was used to
calibrate and wash the dual-electrode sensor, according to
procedures described elsewhere herein. To obtain an increase in
serum glucose to hyperglycemic ranges, a 22.5% dextrose solution
was gradually infused through the animal's left ear vein. The
infusion was stopped once the blood glucose levels reached
sufficiently high blood glucose values and a return to normal
values was followed. Blood samples were collected in 5-minute
intervals from the right jugular vein throughout the study. Plasma
glucose values were determined on an YSI instrument. The study took
about 4-hours.
[1142] FIG. 21A is a graph illustrating test results from an
exemplary dual-electrode continuous glucose sensor coupled to a
flow control system via a catheter inserted in the animal's femoral
vein. The Y-axis represents glucose values (mg/dl) and the X-axis
represents time. The small triangle represents glucose values
provided by the dual-electrode glucose sensor system every 5
minutes, while the small diamond represents substantially
time-corresponding control glucose values obtained from the YSI
device.
[1143] FIG. 21B is a Clark Error Grid quantifying the clinical
accuracy of the blood glucose estimates generated by the
dual-electrode glucose sensor system as compared to a reference
value (e.g., YSI). All values fall within area "A," which indicates
that all values provided by the dual-electrode sensor are within
20% of the values provided by the YSI control test device.
R.sup.2=0.9799.
[1144] The dual-electrode glucose sensor tracked the animal's
glucose values, from about 50-mg/dl to about 300-mg/dl over a
period of about 4-hours. The signals generated by the first and
second working electrodes were processed to provide the data shown
in FIGS. 21A-21B. The glucose values provided by the dual-electrode
sensor tracked very closely with the control measurements provided
by the YSI device. Additionally, all glucose values provided by the
dual-electrode glucose sensor fell within the "A" portion of the
Clark Error Grid. The sensor had an MARD of 7.5% and met the FDA's
ISO standard for hand-held glucose monitors (.+-.15-mg/dl or
.+-.20%) by 100%.
[1145] From these data, the investigators concluded that continuous
IV glucose tracking (via a peripheral vein) using a dual-electrode
continuous glucose sensor, including first and second working
electrodes configured as described herein, coupled with a catheter
and a flow control system can provide consistently accurate glucose
values in vivo.
Example 9
[1146] In vivo glucose data was generated using a dual-electrode
glucose sensor implanted in a host's peripheral vein, as described
elsewhere herein. A flow control system, such as that described
with reference to FIGS. 7-8C, was installed, including a reference
glucose infusion solution (e.g., 100-mg/dl glucose). Upon
initiation, the flow control device began drawing back blood
samples to the glucose sensor, re-infusing the samples and infusing
the reference solution, such as according to the programmed flow
profile. Data were received from the plus-enzyme and no-enzyme
working electrodes, such as described elsewhere herein. The signal
waveforms of the non-enzyme working electrode data (e.g., second
signal waveform) were evaluated to determine if the
draw-back/infusion was successful. For exemplary purposes, one
second signal waveform (from the no-enzyme working electrode)
generated during a known successful infusion and one second signal
waveform generated during a known unsuccessful infusion are
presented.
[1147] FIG. 22 is a graph of a second signal waveform (e.g.,
no-enzyme working electrode data) generated during a successful
infusion of the reference solution into the host versus the
adaptive calibration waveform template. Line 2202 is the adaptive
calibration waveform template. Line 2204 represents the second
signal waveform generated on the non-enzyme electrode during
infusion of the reference solution into the host. The portion of
the graph denoted by 2206 represents the data that could be used to
calibrate the sensor, if the second signal waveform met at least
one criterion. For example, in this experiment, the second signal
waveform substantially overlapped with the adaptive waveform
template. Additionally, the second signal waveform was
substantially monotonic, like the adaptive waveform template. These
facts indicated that the infusion was successful. The second signal
waveform was integrated into the adaptive waveform template, to
generate an updated adaptive waveform template. Additionally, a
data value was displayed on the system's user interface.
[1148] FIG. 23 is a graph of a second signal waveform generated
during an unsuccessful infusion of the reference solution into the
host versus the adaptive calibration waveform template. Line 2302
represents the adaptive calibration waveform template. Line 2304
represents the second signal waveform generated on the non-enzyme
electrode during the unsuccessful infusion of the reference
solution into the host. The portion of the graph denoted by 2306
represents the data that could have been used to calibrate the
sensor, if the second signal waveform had met at least one
criterion. Lines 2302 and 2304 substantially overlapped and had a
negative slope, until about 70 sample points. At about 70 sample
points, line 2304 exhibited a substantial peak. A second increase
began at about 110 sample points and extended to 120 sample points,
when the waveform ended. During this deviation (e.g., 2306) the
second signal waveform did not correlate with the adaptive
template. Additionally, the second signal waveform was not
monotonic. These data indicated that the infusion was not
successful and the system was not reliable. The signal waveform was
not integrated with the adaptive template. The signal data denoted
by 2306 and corresponding generated first signal data were not used
to calibrate the sensor.
Example 10
[1149] In vivo glucose data was generated using a dual-electrode
glucose sensor implanted in a host's peripheral vein, as described
elsewhere herein. A flow control system, such as that described
with reference to FIGS. 7-8C was installed, including a reference
glucose infusion solution (e.g., 100-mg/dl glucose). Upon
initiation, the flow control device began drawing back blood
samples to the glucose sensor, re-infusing the samples and infusing
the reference solution, such as according to the programmed flow
profile.
[1150] FIG. 24 is a graph of the signal generated from the
plus-enzyme working electrode (black diamonds) and from the
no-enzyme working electrode (black dots). Completion of sensor
break-in is denoted by the dashed vertical line. The sensor was
implanted in the host at about 2:00 P.M. Upon drawing-back a
sample, the signal waveform increased. Upon re-infusion of the
sample and infusion of the reference solution, the signal waveform
decreased. Accordingly, with each cycle of sample draw-back and
infusion, a signal peak and valley were generated. Upon sensor
start-up, the sensor signal (e.g., baseline), on both working
electrodes, started high (e.g., .about.400-500 counts) and then
drifted progressively downward over time (e.g., baseline drift). In
this example, wherein the sensor system included a dual electrode
sensor, and both electrochemical break-in (illustrated by the
exponential decay during the first 30 minutes after sensor
start-up) and membrane break-in (illustrated by a difference
between the enzyme signal and non-enzyme signal during the first 30
minutes after sensor start-up) can be seen. After about the first
30 minutes, the sensor data, notably the second signal waveform
(e.g., no-enzyme working electrode data), stabilized.
Example 11
[1151] In vivo glucose data was generated using a dual-electrode
glucose sensor implanted in a host's peripheral vein, as described
elsewhere herein. A flow control system, such as that described
with reference to FIGS. 7-8C were installed, including a reference
glucose infusion solution (e.g., 100 mg/dL glucose). Upon
initiation, the flow control device began drawing back blood
samples to the glucose sensor, re-infusing the samples and infusing
the reference solution, such as according to the programmed flow
profile.
[1152] FIG. 25 is a graph of calculated sensor sensitivities. The
Y-axis represents sensor sensitivity (in pA/mg/dL). The X-axis
represents time (e.g., of sensor implantation/use). Each point
represents an individual sensitivity calculation determined using a
subtracted signal from the dual-electrode sensor, wherein the
sensitivity was determined when the sensor was exposed to the 100
mg/dL reference solution, as described in more detail elsewhere
herein. Change in calculated sensor sensitivity was evaluated over
short time periods (e.g., also referred to as short-term
sensitivity evaluation; every 5-minutes) throughout sensor use, and
over longer time periods (e.g., also referred to as long-term
sensitivity evaluation) the total change in sensor sensitivity
between the calculated sensor sensitivity at t=0 and at t=1-hr, and
between t=1-hr and t=2-hr). The change in sensitivity was
calculated using the formula (m.sub.2-m.sub.1)/m.sub.1. For the
first hour of sensor use, when the sensor was breaking in and
dramatic changes in sensitivity are observed, a change in
sensitivity threshold was set at .+-.100% over the hour. For the
second hour of sensor use, when changes in sensitivity begin to
level off, the threshold was set at .+-.20%. For short time
sensitivity evaluation, the threshold was set at a .+-.15% change
in sensor sensitivity over 5-minutes. An example of 5 minute time
period is shown at 2502. The calculated sensitivity at point 2502a
was 2.2 pA/mg/dL and the calculated sensitivity at point 2502b was
also 2.2 pA/mg/dL, resulting in a sensitivity change of 0% in
5-minutes. Accordingly, the change in sensitivity between these two
time points was well within the .+-.15% per 5-minutes threshold. An
example of sensitivity drift during the first hour of sensor use is
denoted by 2504. At 2504a, the sensitivity was 1.5 pA/mg/dL. At
2504b, the sensitivity was about 2.2 pA/mg/dL, giving a 70% change
in sensitivity over the first hour of sensor use. Accordingly, the
increase in sensor sensitivity, during the first hour of sensor
use, was within the .+-.100% threshold. Another example of
sensitivity drift, during the second hour of sensor use, is denoted
by 2506. For the second hour of sensor use, the threshold was set
at .+-.20% over the second hour. Again, at 2504b, the sensitivity
was about 2.2 pA/mg/dL. At point 2506a, the sensitivity was 2.4
pA/mg/dL, giving a 20% drift in sensitivity, which met the .+-.20%
threshold.
Example 12: Pain Monitoring by Continuous Intra-Vascular Glucose
Detection in the Neonatal Host
[1153] A newborn infant (the host) is transferred to the newborn
intensive care unit (NICU) soon after birth. When the host arrives,
a nurse inserts a 24-gauge catheter into one of the host's veins.
The nurse inserts a continuous glucose sensor (e.g., see FIG. 1F)
into the catheter and connects the fluid coupler to the catheter's
hub. The sensor is configured such that it extends into the
catheter's lumen such that the electroactive surface(s) are located
adjacent to the catheter's orifice. Then the nurse sets up the
fluid control device (e.g., see FIG. 10A) with an infusion
solution, and connects the IV tubing to the fluid coupler. The
nurse initiates the system and selects a flow profile optimized for
a neonatal host. For example, the flow profile directs the drawback
of minimum sample volumes (e.g., about 1, 2, 3, 4 or 5-.mu.l),
return of the sample to the host, and sensor washing using minimum
volumes (e.g., about 10, 20, 30, 50 or 100-.mu.l of solution). The
system begins continuously monitoring the host's blood glucose
level and to display the host's blood glucose level. After a period
of time, the host's blood glucose begins to rise. The host's blood
glucose exceeds a first programmed range (e.g., a euglycemic range)
and the processor module provides an alarm to the nurse and/or to
display at least one of an instruction to the nurse, the host's
glucose level, and an indication of the host's level of comfort
(e.g., pain, distress), wherein the level of the comfort is
associated with the host's glucose concentration. For example, the
nurse is alerted that the host is beginning to become distressed
and may be feeling pain. The system is configured to instruct the
nurse to check the host's vital signs and to provide appropriate
care for the host's observed condition. The host's blood glucose
continues to increase and exceeds a second programmed range (e.g.,
a hyperglycemic range). The system provides an alarm, which alerts
the nurse to an increase in the host's distressed condition.
Additionally, the system displays at least one of updated
instructions to the nurse, the host's blood glucose level, and/or
an indication of the host's pain level, wherein the pain level is
associated with the host's blood glucose level. Upon checking on
the host, the nurse observes that the host appears to be in pain,
and follows instructions displayed on the display to administer
pain medication. Alternatively, the system can be configured to
automatically infuse basal and/or bolus amounts of pain medication
based at least in part on the measured glucose concentration. As
the pain medication becomes effective, the host's blood glucose
begins to return to the first programmed range. The system displays
at least one of the host's blood glucose level and/or an indication
of the host's comfort (e.g., pain, distress) level, wherein the
indication of the host's comfort level is associated with the
host's glucose level.
[1154] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Pat. Nos. 4,994,167; 4,757,022; 6,001,067; 6,741,877; 6,702,857;
6,558,321; 6,931,327; 6,862,465; 7,074,307; 7,081,195; 7,108,778;
7,110,803; 7,192,450; 7,226,978; 7,310,544; 7,364,592; 7,366,556;
and 7,424,318.
[1155] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Patent Publication No. US-2005-0143635-A1; U.S. Patent Publication
No. US-2005-0181012-A1; U.S. Patent Publication No.
US-2005-0177036-A1; U.S. Patent Publication No. US-2005-0124873-A1;
U.S. Patent Publication No. US-2005-0115832-A1; U.S. Patent
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[1156] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
patent application Ser. No. 09/447,227 filed Nov. 22, 1999 and
entitled "DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S.
patent application Ser. No. 11/654,135 filed Jan. 17, 2007 and
entitled "POROUS MEMBRANES FOR USE WITH IMPLANTABLE DEVICES"; U.S.
patent application Ser. No. 11/654,140 filed Jan. 17, 2007 and
entitled "MEMBRANES FOR AN ANALYTE SENSOR"; U.S. patent application
Ser. No. 11/691,426 filed Mar. 26, 2007 and entitled "ANALYTE
SENSOR"; U.S. patent application Ser. No. 12/103,594 filed Apr. 15,
2008 and entitled "BIOINTERFACE WITH MACRO- AND
MICRO-ARCHITECTURE"; U.S. patent application Ser. No. 12/113,724
filed May 1, 2008 and entitled "LOW OXYGEN IN VIVO ANALYTE SENSOR";
U.S. patent application Ser. No. 12/055,098 filed Mar. 25, 2008 and
entitled "ANALYTE SENSOR"; U.S. patent application Ser. No.
12/054,953 filed Mar. 25, 2008 and entitled "ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/055,114 filed Mar. 25, 2008 and
entitled "ANALYTE SENSOR"; U.S. patent application Ser. No.
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DELIVERY DEVICE FOR USE WITH CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/133,761 filed Jun. 5, 2008 and
entitled "INTEGRATED MEDICAMENT DELIVERY DEVICE FOR USE WITH
CONTINUOUS ANALYTE SENSOR"; U.S. patent application Ser. No.
12/133,738 filed Jun. 5, 2008 and entitled "INTEGRATED MEDICAMENT
DELIVERY DEVICE FOR USE WITH CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/139,305 filed Jun. 13, 2008 and
entitled "ELECTRODE SYSTEMS FOR ELECTROCHEMICAL SENSORS"; U.S.
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RECEIVER FOR CONTINUOUS ANALYTE SENSOR"; U.S. patent application
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RECEIVER FOR CONTINUOUS ANALYTE SENSOR"; U.S. patent application
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METHODS FOR PROCESSING ANALYTE SENSOR DATA"; U.S. patent
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entitled "IMPLANTABLE ANALYTE SENSOR"; U.S. patent application Ser.
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entitled "SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/253,120 filed Oct. 16, 2008 and
entitled "SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/253,064 filed Oct. 16, 2008 and
entitled "SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/252,996 filed Oct. 16, 2008 and
entitled "SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR"; U.S.
patent application Ser. No. 12/252,967 filed Oct. 16, 2008 and
entitled "SIGNAL PROCESSING FOR CONTINUOUS ANALYTE SENSOR"; U.S.
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patent application Ser. No. 12/260,017 filed Oct. 28, 2008 and
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[1157] All references cited herein, including but not limited to
published and unpublished applications, patents, and literature
references, are incorporated herein by reference in their entirety
and are hereby made a part of this specification. 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.
[1158] 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.
[1159] All numbers expressing quantities of ingredients, reaction
conditions, and so forth used in the specification 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 herein are approximations that may vary
depending upon the desired properties sought to be obtained. At the
very least, and not as an attempt to limit the application of the
doctrine of equivalents to the scope of any claims in any
application claiming priority to the present application, each
numerical parameter should be construed in light of the number of
significant digits and ordinary rounding approaches.
[1160] The above description discloses several methods and
materials of the present invention. This invention is susceptible
to modifications in the methods and materials, as well as
alterations in the fabrication methods and equipment. Such
modifications will become apparent to those skilled in the art from
a consideration of this disclosure or practice of the invention
disclosed herein. Consequently, it is not intended that this
invention be limited to the specific embodiments disclosed herein,
but that it cover all modifications and alternatives coming within
the true scope and spirit of the invention.
* * * * *