U.S. patent application number 11/543396 was filed with the patent office on 2008-05-22 for analyte sensor.
Invention is credited to Mark Brister, James R. Petisce, Sean Saint, Vance Swanson.
Application Number | 20080119703 11/543396 |
Document ID | / |
Family ID | 39323923 |
Filed Date | 2008-05-22 |
United States Patent
Application |
20080119703 |
Kind Code |
A1 |
Brister; Mark ; et
al. |
May 22, 2008 |
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 a host's peripheral vein or
artery.
Inventors: |
Brister; Mark; (Encinitas,
CA) ; Saint; Sean; (San Diego, CA) ; Swanson;
Vance; (San Diego, CA) ; Petisce; James R.;
(San Diego, CA) |
Correspondence
Address: |
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Family ID: |
39323923 |
Appl. No.: |
11/543396 |
Filed: |
October 4, 2006 |
Current U.S.
Class: |
600/347 ;
600/365 |
Current CPC
Class: |
A61B 5/1495 20130101;
A61B 5/6848 20130101; A61M 5/1723 20130101; A61M 2230/201 20130101;
A61B 5/14532 20130101; A61B 5/6849 20130101; A61B 5/14542 20130101;
A61M 5/16804 20130101; A61B 5/1473 20130101; A61M 5/14 20130101;
A61B 5/412 20130101; A61B 5/14546 20130101; A61B 2560/0223
20130101; A61B 5/14865 20130101 |
Class at
Publication: |
600/347 ;
600/365 |
International
Class: |
A61B 5/05 20060101
A61B005/05; A61B 5/00 20060101 A61B005/00 |
Claims
1. A system for measuring an analyte, the system comprising: a
vascular access device in communication with a vascular system of a
host; and an analyte sensor configured to extend within the
vascular access device, wherein the analyte sensor is configured to
measure a concentration of an analyte within the vascular
system.
2. The system of claim 1, wherein the analyte sensor is configured
to extend through the vascular access device and into a blood
stream of the host.
3. The system of claim 1, wherein the vascular access device is a
catheter.
4. The system of claim 1, wherein the vascular access device is
configured for insertion into a vein of the host.
5. The system of claim 1, wherein the vascular access device is
configured for insertion into an artery of the host.
6. The system of claim 1, wherein the vascular access device is
configured to operatively couple to a pressure transducer for
measurement of a blood pressure of the host.
7. The system of claim 1, wherein the vascular access device is
configured to operatively couple to a blood chemistry analysis
device for measuring a blood chemistry of the host.
8. The system of claim 1, wherein the analyte sensor is a glucose
sensor.
9. The system of claim 1, further comprising a sheath configured to
protect the analyte sensor during insertion of the analyte sensor
into the catheter.
10. The system of claim 9, wherein the sheath comprises a slot
configured to allow the release of the analyte sensor
therefrom.
11. The system of claim 1, further comprising a fluid coupler
having first end and second end, wherein the fluid coupler is
configured to mate with the vascular access device on the first
end, and wherein at least a portion of the analyte sensor extends
through the fluid coupler or is housed within the fluid
coupler.
12. The system of claim 11, wherein the fluid coupler comprises
sensor electronics formed thereon.
13. The system of claim 12, wherein the sensor electronics comprise
a potentiostat.
14. The system of claim 11, wherein the fluid coupler is configured
to mate with a medical device on the second end.
15. The system of claim 14, wherein the medical device comprises at
least one device selected from the group consisting of a blood
pressure monitor, a blood chemistry device, and a dialysis bypass
machine.
16. The system of claim 1, wherein the analyte sensor is configured
to extend through the vascular access device and into a blood
stream of the host by from about 0.010 inches to about 1 inch.
17. The system of claim 1, wherein the vascular access device and
the analyte sensor are configured to indwell within a blood stream
of the host in vivo.
18. The system of claim 1, further comprising sensor electronics
operatively connected to the analyte sensor.
19. The system of claim 18, wherein the analyte sensor comprises at
least one working electrode configured to measure a first
signal.
20. The system of claim 19, wherein the first signal is
substantially analyte related.
21. The system of claim 19, wherein the analyte sensor further
comprises a second working electrode configured to measure a second
signal.
22. The system of claim 21, wherein the second signal is
substantially non-analyte related.
23. The system of claim 22, wherein the sensor electronics are
configured to process the second signal and the first signal to
determine a concentration of an analyte.
24. The system of claim 19, further comprising a reference
electrode.
25. The system of claim 24, wherein the reference electrode is
located at a position remote from the working electrode.
26. The system of claim 25, further comprising a fluid coupler
having first end and a second end, wherein the fluid coupler is
configured to mate with the catheter on the first end, wherein at
least a portion of the analyte sensor extends through the fluid
coupler or is housed within the fluid coupler, and wherein the
reference electrode is located at a position proximal to the fluid
coupler or within the fluid coupler.
27. The system of claim 1, wherein an end of the analyte sensor
that extends into a blood stream of the host comprises an enlarged
area.
28. The system of claim 1, wherein a substantial portion of the
analyte sensor has a diameter of less than about 0.008 inches.
29. The system of claim 1, wherein a substantial portion of the
analyte sensor has a diameter of less than about 0.004 inches.
30. The system of claim 1, wherein the analyte sensor further
comprises a bioinert material or a bioactive agent incorporated
therein or thereon.
31. The system of claim 30, wherein the bioactive agent comprises
at least one agent selected from the group consisting of vitamin K
antagonists, heparin group anticoagulants, platelet aggregation
inhibitors, enzymes, direct thrombin inhibitors, Dabigatran,
Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban.
32. The system of claim 1, wherein the analyte sensor comprises a
working electrode and a reference electrode, and wherein at least
one of the working electrode and the reference electrode comprises
a wire.
33. The system of claim 1, wherein the analyte sensor comprises a
working electrode and a reference electrode, wherein the working
electrode and the reference electrode are both wires, and wherein
the wires are coaxial.
34. The system of claim 1, wherein the analyte sensor comprises a
working electrode and a reference electrode, wherein the working
electrode and the reference electrode are both wires, and wherein
the wires are juxtapositioned.
35. The system of claim 1, wherein the analyte sensor comprises a
working electrode and a reference electrode, wherein the working
electrode and the reference electrode are both wires, and wherein
the reference electrode is helically wound around the working
electrode.
36. The system of claim 1, wherein the analyte sensor comprises a
working electrode, and wherein the working electrode is
flexible.
37. The system of claim 1, wherein the analyte sensor comprises a
working electrode, and wherein the working electrode has a variable
stiffness.
38. The system of claim 1, wherein the analyte sensor comprises at
least one wire having a helical configuration, and wherein a
variable stiffness in the helical wire is provided by at least one
of a variable pitch of the helical wire and a variable
cross-section of the helical wire.
39. A method for measuring an analyte in a blood stream of a host,
the method comprising: inserting a vascular access device into
communication with a blood stream of a host; and inserting an
analyte sensor into the vascular access device, wherein the analyte
sensor measures a concentration of an analyte within the blood
stream of the host.
40. The method of claim 39, wherein the analyte sensor extends
through the vascular access device and into the blood stream.
41. The method of claim 39, wherein the vascular access device is a
catheter.
42. The method of claim 39, wherein the vascular access device is
inserted into a vein of the host.
43. The method of claim 39, wherein the vascular access device is
inserted into an artery of the host.
44. The method of claim 39, further comprising coupling a pressure
transducer to the analyte sensor.
45. The system of claim 39, further comprising coupling a blood
chemistry analysis device to the analyte sensor.
46. The method of claim 39, wherein the analyte sensor measures
glucose.
47. The method of claim 39, wherein the analyte sensor comprises a
fluid coupler for housing the analyte sensor or supporting the
analyte sensor, and wherein the method further comprises mating the
fluid coupler with the vascular access device on a first end of the
fluid coupler.
48. The method of claim 47, further comprising mating the fluid
coupler with a medical device on a second end of the fluid
coupler.
49. The method of claim 48, further comprising measuring at least
one other parameter with the medical device, wherein the parameter
is selected from the group consisting of blood pressure and blood
chemistry.
50. The method of claim 39, wherein the step of inserting the
analyte sensor comprises inserting the analyte sensor beyond an in
vivo end of the vascular access device by from about 0.010 inches
to about 1 inch.
51. The method of claim 39, wherein the vascular access device and
the analyte sensor are configured to indwell within a blood stream
of the host in vivo.
52. The method of claim 39, further comprising sensor electronics
operatively connected to the analyte sensor, wherein the method
further comprises utilizing sensor electronics to measure a
concentration of an analyte within the host.
53. The method of claim 52, wherein the analyte sensor comprises at
least one working electrode, and wherein the method further
comprises measuring a first signal at the working electrode, and
wherein the first signal is substantially analyte-related.
54. The method of claim 53, wherein the analyte sensor further
comprises a second working electrode, and wherein the method
further comprises measuring a second signal at the second working
electrode.
55. The method of claim 54, wherein the second signal is
substantially non-analyte-related.
56. The method of claim 55, further comprising processing the
second signal and the first signal to determine a concentration of
an analyte.
57. The method of claim 39, further comprising avoiding piercing of
a blood vessel during sensor insertion into the blood vessel by
providing an enlarged area at an insertion end of the analyte
sensor.
58. The method of claim 39, further comprising substantially
preventing clotting or thrombosis proximal to or on the analyte
sensor within the blood stream.
Description
FIELD OF THE INVENTION
[0001] The preferred embodiments relate generally to systems and
methods for measuring an analyte in a host.
BACKGROUND OF THE INVENTION
[0002] Diabetes mellitus is a disorder in which the pancreas cannot
create sufficient insulin (Type I or insulin dependent) and/or in
which insulin is not effective (Type 2 or non-insulin dependent).
In the diabetic state, the victim suffers from high blood sugar,
which 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.
[0003] Conventionally, a person with diabetes carries a
self-monitoring blood glucose (SMBG) monitor, which typically
requires uncomfortable finger pricking methods. Due to the lack of
comfort and convenience, a person with diabetes normally only
measures his or her glucose levels two to four times per day.
Unfortunately, such time intervals are so far spread apart that the
person with diabetes likely finds out too late of a hyperglycemic
or hypoglycemic condition, sometimes incurring dangerous side
effects. It is not only unlikely that a person with diabetes will
take a timely SMBG value, it is also likely that he or she will not
know if his or her blood glucose value is going up (higher) or down
(lower) based on conventional methods. This inhibits the ability to
make educated insulin therapy decisions.
[0004] 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
[0005] In a first aspect, a system for measuring an analyte is
provided, the system comprising a vascular access device in
communication with a vascular system of a host; and an analyte
sensor configured to extend within the vascular access device,
wherein the analyte sensor is configured to measure a concentration
of an analyte within the vascular system.
[0006] In an embodiment of the first aspect, the analyte sensor is
configured to extend through the vascular access device and into a
blood stream of the host.
[0007] In an embodiment of the first aspect, the vascular access
device is a catheter.
[0008] In an embodiment of the first aspect, the vascular access
device is configured for insertion into a vein of the host.
[0009] In an embodiment of the first aspect, the vascular access
device is configured for insertion into an artery of the host.
[0010] In an embodiment of the first aspect, the vascular access
device is configured to operatively couple to a pressure transducer
for measurement of a blood pressure of the host.
[0011] In an embodiment of the first aspect, the vascular access
device is configured to operatively couple to a blood chemistry
analysis device for measuring a blood chemistry of the host.
[0012] In an embodiment of the first aspect, the analyte sensor is
a glucose sensor.
[0013] In an embodiment of the first aspect, the system further
comprises a sheath configured to protect the analyte sensor during
insertion of the analyte sensor into the catheter. The sheath can
comprise a slot configured to allow the release of the analyte
sensor therefrom.
[0014] In an embodiment of the first aspect, the system further
comprises a fluid coupler having first end and second end, wherein
the fluid coupler is configured to mate with the vascular access
device on the first end, and wherein at least a portion of the
analyte sensor extends through the fluid coupler or is housed
within the fluid coupler. The fluid coupler can comprise sensor
electronics formed thereon. The sensor electronics can a
potentiostat. The fluid coupler can be configured to mate with a
medical device on the second end. The medical device can comprise
at least one device selected from the group consisting of a blood
pressure monitor, a blood chemistry device, and a dialysis bypass
machine.
[0015] In an embodiment of the first aspect, the analyte sensor is
configured to extend through the vascular access device and into a
blood stream of the host by from about 0.010 inches to about 1
inch.
[0016] In an embodiment of the first aspect, the vascular access
device and the analyte sensor are configured to indwell within a
blood stream of the host in vivo.
[0017] In an embodiment of the first aspect, further comprising
sensor electronics operatively connected to the analyte sensor.
[0018] In an embodiment of the first aspect, the analyte sensor
comprises at least one working electrode configured to measure a
first signal. The first signal can be substantially analyte
related.
[0019] In an embodiment of the first aspect, the analyte sensor
further comprises a second working electrode configured to measure
a second signal. The second signal can be substantially non-analyte
related.
[0020] In an embodiment of the first aspect, the sensor electronics
are configured to process the second signal and the first signal to
determine a concentration of an analyte.
[0021] In an embodiment of the first aspect, the sensor further
comprises a reference electrode.
[0022] In an embodiment of the first aspect, the reference
electrode is located at a position remote from the working
electrode.
[0023] In an embodiment of the first aspect, the sensor further
comprises a fluid coupler having first end and a second end,
wherein the fluid coupler is configured to mate with the catheter
on the first end, wherein at least a portion of the analyte sensor
extends through the fluid coupler or is housed within the fluid
coupler, and wherein the reference electrode is located at a
position proximal to the fluid coupler or within the fluid
coupler.
[0024] In an embodiment of the first aspect, an end of the analyte
sensor that extends into a blood stream of the host comprises an
enlarged area.
[0025] In an embodiment of the first aspect, a substantial portion
of the analyte sensor has a diameter of less than about 0.008
inches.
[0026] In an embodiment of the first aspect, a substantial portion
of the analyte sensor has a diameter of less than about 0.004
inches.
[0027] In an embodiment of the first aspect, the analyte sensor
further comprises a bioinert material or a bioactive agent
incorporated therein or thereon. The bioactive agent can comprise
at least one agent selected from the group consisting of vitamin K
antagonists, heparin group anticoagulants, platelet aggregation
inhibitors, enzymes, direct thrombin inhibitors, Dabigatran,
Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban.
[0028] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein at
least one of the working electrode and the reference electrode
comprises a wire.
[0029] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are coaxial.
[0030] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are juxtapositioned.
[0031] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the reference electrode is helically wound around the
working electrode.
[0032] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode is
flexible.
[0033] In an embodiment of the first aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode
has a variable stiffness.
[0034] In an embodiment of the first aspect, the analyte sensor
comprises at least one wire having a helical configuration, wherein
a variable stiffness in the helical wire is provided by at least
one of a variable pitch of the helical wire and a variable
cross-section of the helical wire.
[0035] In a second aspect, a method for measuring an analyte in a
blood stream of a host is provided, the method comprising inserting
a vascular access device into communication with a blood stream of
a host; and inserting an analyte sensor into the vascular access
device, wherein the analyte sensor measures a concentration of an
analyte within the blood stream of the host.
[0036] In an embodiment of the second aspect, the analyte sensor
extends through the vascular access device and into the blood
stream.
[0037] In an embodiment of the second aspect, the vascular access
device is a catheter.
[0038] In an embodiment of the second aspect, the vascular access
device is inserted into a vein of the host.
[0039] In an embodiment of the second aspect, the vascular access
device is inserted into an artery of the host.
[0040] In an embodiment of the second aspect, the method further
comprises coupling a pressure transducer to the analyte sensor.
[0041] In an embodiment of the second aspect, the method further
comprises coupling a blood chemistry analysis device to the analyte
sensor.
[0042] In an embodiment of the second aspect, the analyte sensor
measures glucose.
[0043] In an embodiment of the second aspect, the analyte sensor
comprises a fluid coupler for housing the analyte sensor or
supporting the analyte sensor, and wherein the method further
comprises mating the fluid coupler with the vascular access device
on a first end of the fluid coupler.
[0044] In an embodiment of the second aspect, the method further
comprises mating the fluid coupler with a medical device on a
second end of the fluid coupler.
[0045] In an embodiment of the second aspect, the method further
comprises measuring at least one other parameter with the medical
device, wherein the parameter is selected from the group consisting
of blood pressure and blood chemistry.
[0046] In an embodiment of the second aspect, the step of inserting
the analyte sensor comprises inserting the analyte sensor beyond an
in vivo end of the vascular access device by from about 0.010
inches to about 1 inch.
[0047] In an embodiment of the second aspect, the vascular access
device and the analyte sensor are configured to indwell within a
blood stream of the host in vivo.
[0048] In an embodiment of the second aspect, sensor electronics
are operatively connected to the analyte sensor, and wherein the
method further comprises utilizing sensor electronics to measure a
concentration of an analyte within the host.
[0049] In an embodiment of the second aspect, the analyte sensor
comprises at least one working electrode, and wherein the method
further comprises measuring a first signal at the working
electrode, and wherein the first signal is substantially
analyte-related.
[0050] In an embodiment of the second aspect, the analyte sensor
further comprises a second working electrode, and wherein the
method further comprises measuring a second signal at the second
working electrode. The second signal can be substantially
non-analyte-related.
[0051] In an embodiment of the second aspect, the method further
comprises processing the second signal and the first signal to
determine a concentration of an analyte.
[0052] In an embodiment of the second aspect, the method further
comprises avoiding piercing of a blood vessel during sensor
insertion into the blood vessel by providing an enlarged area at an
insertion end of the analyte sensor.
[0053] In an embodiment of the second aspect, the method further
comprises substantially preventing clotting or thrombosis proximal
to or on the analyte sensor within the blood stream.
[0054] In a third aspect, a system for measuring an analyte is
provided, the system comprising a vascular access device configured
for insertion communication with a vascular system of a host,
wherein the vascular access device comprises an analyte sensor at
least partially integrally incorporated therewith; and sensor
electronics operatively connected to the analyte sensor, wherein
the sensor electronics are configured to measure a concentration of
an analyte within the vascular system.
[0055] In an embodiment of the third aspect, the sensor electronics
are configured to substantially continuously measure the analyte
concentration.
[0056] In an embodiment of the third aspect, the analyte is
glucose.
[0057] In an embodiment of the third aspect, the vascular access
device is configured to operatively couple to a blood chemistry
analysis device for measuring a blood chemistry of the host.
[0058] In an embodiment of the third aspect, the analyte sensor
comprises at least one working electrode configured measure a first
signal.
[0059] In an embodiment of the third aspect, the first signal is
substantially analyte related.
[0060] In an embodiment of the third aspect, the analyte sensor
further comprises a second working electrode configured measure a
second signal.
[0061] In an embodiment of the third aspect, the second signal is
substantially non-analyte related.
[0062] In an embodiment of the third aspect, the sensor electronics
are configured to process the second signal and the first signal to
determine a concentration of an analyte.
[0063] In an embodiment of the third aspect, the analyte sensor
further comprises a reference electrode.
[0064] In an embodiment of the third aspect, the reference
electrode is located at a position remote from the reference
electrode.
[0065] In an embodiment of the third aspect, the reference
electrode is configured to be located outside of a blood stream of
the host.
[0066] In an embodiment of the third aspect, the analyte sensor
further comprises a counter electrode.
[0067] In an embodiment of the third aspect, the analyte sensor is
configured to at least partially contact an in vivo blood stream of
the host when the vascular access device is inserted therein.
[0068] In an embodiment of the third aspect, the analyte sensor is
deposited on an exterior surface of the vascular access device.
[0069] In an embodiment of the third aspect, the analyte sensor is
electroplated onto the exterior surface of the vascular access
device.
[0070] In an embodiment of the third aspect, the analyte sensor is
wired to at least a portion of the sensor electronics.
[0071] In an embodiment of the third aspect, the analyte sensor is
wirelessly connected to at least a portion of the sensor
electronics.
[0072] In an embodiment of the third aspect, the vascular access
device is a catheter.
[0073] In an embodiment of the third aspect, the analyte sensor
further comprises a bioinert material or a bioactive agent
incorporated therewith. The bioactive agent can comprise at least
one agent selected from the group consisting of vitamin K
antagonists, heparin group anticoagulants, platelet aggregation
inhibitors, enzymes, direct thrombin inhibitors, Dabigatran,
Defibrotide, Dermatan sulfate, Fondaparinux, and Rivaroxaban.
[0074] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode and a reference electrode, and
wherein at least one of the working electrode and the reference
electrode comprises a wire.
[0075] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are coaxial.
[0076] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are juxtapositioned.
[0077] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the reference electrode is helically wound around the
working electrode.
[0078] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode is
flexible.
[0079] In an embodiment of the third aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode
has a variable stiffness.
[0080] In an embodiment of the third aspect, the analyte sensor
comprises at least one wire having a helical configuration, and
wherein a variable stiffness in the helical wire is provided by at
least one of a variable pitch of the helical wire and a variable
cross-section of the helical wire.
[0081] In a fourth aspect, a method for measuring an analyte in a
blood stream of a host is provided, the method comprising inserting
a vascular access device into communication with a blood stream of
a host, wherein the vascular access device comprises an analyte
sensor at least partially integrally incorporated therewith;
operatively connecting the analyte sensor to sensor electronics;
and measuring an analyte concentration in the host.
[0082] In an embodiment of the fourth aspect, the method further
comprises substantially continuously measuring an analyte
concentration.
[0083] In an embodiment of the fourth aspect, the step of measuring
an analyte concentration comprises measuring a glucose
concentration.
[0084] In an embodiment of the fourth aspect, the analyte sensor
comprises at least one working electrode, wherein the measuring
step comprises measuring a first signal at the working electrode,
wherein the first signal is substantially analyte-related.
[0085] In an embodiment of the fourth aspect, the analyte sensor
further comprises a second working electrode, and the measuring
step further comprises measuring a second signal at the second
working electrode, wherein the second signal is substantially
non-analyte related.
[0086] In an embodiment of the fourth aspect, the method further
comprises processing the second signal and the first signal to
determine a concentration of an analyte.
[0087] In an embodiment of the fourth aspect, the measuring step
comprises measuring an analyte concentration in an in vivo blood
stream of the host.
[0088] In an embodiment of the fourth aspect, the operatively
connecting step comprises connecting the analyte sensor to at least
a portion of the sensor electronics via a wired connection.
[0089] In an embodiment of the fourth aspect, the operatively
connecting step comprises connecting the analyte sensor to at least
a portion of the sensor electronics via a wireless connection.
[0090] In a fifth aspect, a method for manufacturing an analyte
sensor configured for measuring an analyte in a vascular system of
a host is provided, the method comprising providing a vascular
access device; and at least partially integrally incorporating an
analyte sensor in the vascular access device or on a surface of the
vascular access device.
[0091] In an embodiment of the fifth aspect, the step of at least
partially integrally incorporating an analyte sensor comprises
depositing at least one working electrode on an interior surface of
the vascular access device or on an exterior surface of the
vascular access device.
[0092] In an embodiment of the fifth aspect, the depositing step
further comprises electroplating the working electrode onto the
exterior surface of the vascular access device.
[0093] In an embodiment of the fifth aspect, the step of at least
partially integrally incorporating an analyte sensor further
comprises depositing a second working electrode on an interior
surface of the vascular access device or on an exterior surface of
the vascular access device.
[0094] In an embodiment of the fifth aspect, the step of at least
partially integrally incorporating an analyte sensor further
comprises depositing a reference electrode on an interior surface
of the vascular access device or on an exterior surface of the
vascular access device.
[0095] In an embodiment of the fifth aspect, the step of at least
partially integrally incorporating an analyte sensor further
comprises depositing a counter electrode on an interior surface of
the vascular access device or on an exterior surface of the
vascular access device.
[0096] In an embodiment of the fifth aspect, the surface of the
vascular access device is selected from the group consisting of an
exterior surface, an interior surface, and a tip surface.
[0097] In an embodiment of the fifth aspect, the step of at least
partially integrally incorporating an analyte sensor further
comprises forming a reference electrode at a location remote from
the working electrode.
[0098] In a sixth aspect, a method for calibrating a continuous
analyte sensor in a host is provided, the method comprising
inserting a continuous analyte sensor into a host; contacting a
calibration solution with at least a portion of the continuous
analyte sensor; and calibrating the continuous analyte sensor to
provide calibrated analyte sensor data comprising at least one
calibrated sensor data point.
[0099] In an embodiment of the sixth aspect, the continuous analyte
sensor is configured to indwell within a blood stream of a
host.
[0100] In an embodiment of the sixth aspect, the continuous analyte
sensor is configured to measure a glucose concentration in the
host.
[0101] In an embodiment of the sixth aspect, the calibration
solution comprises a predetermined amount of glucose.
[0102] In an embodiment of the sixth aspect, the method further
comprises displaying the calibrated analyte sensor data.
[0103] In an embodiment of the sixth aspect, the method further
comprises contacting an additional calibration solution with at
least a portion of the continuous analyte sensor.
[0104] In an embodiment of the sixth aspect, the method further
comprises calibrating or re-calibrating the continuous analyte
sensor to provide calibrated analyte sensor data comprising at
least one calibrated sensor data point.
[0105] In an embodiment of the sixth aspect, the step of contacting
an additional calibration solution is repeated.
[0106] In an embodiment of the sixth aspect, the step of contacting
an additional calibration solution is performed automatically.
[0107] In an embodiment of the sixth aspect, the step of contacting
an additional calibration solution is performed manually.
[0108] In an embodiment of the sixth aspect, the method further
comprises contacting a non-analyte solution with at least a portion
of the continuous analyte sensor to flush the sensor.
[0109] In an embodiment of the sixth aspect, the step of contacting
a non-analyte solution is performed prior to the step of contacting
a calibration solution with at least a portion of the continuous
analyte sensor.
[0110] In a seventh aspect, a method for calibrating a continuous
analyte sensor in a host is provided, the method comprising
inserting a continuous analyte sensor system into a host;
withdrawing at least one blood sample from the host; measuring a
reference analyte value from the blood sample; and calibrating the
continuous analyte sensor to provide calibrated analyte sensor data
comprising at least one calibrated sensor data point.
[0111] In an embodiment of the seventh aspect, the continuous
analyte sensor is configured to indwell within a blood stream of
the host.
[0112] In an embodiment of the seventh aspect, the continuous
analyte sensor is configured to measure a glucose concentration of
the host.
[0113] In an embodiment of the seventh aspect, the step of
withdrawing at least one blood sample from the host is performed
automatically.
[0114] In an embodiment of the seventh aspect, the step of
inserting a continuous analyte sensor comprises inserting a
vascular access device into communication with a vascular system of
the host, wherein the sensor is integrally incorporated with the
vascular access device.
[0115] In an embodiment of the seventh aspect, the step of
withdrawing comprises withdrawing a blood sample through the
vascular access device.
[0116] In an embodiment of the seventh aspect, the method further
comprises inserting a vascular access device into communication
with a vascular system of the host, wherein the sensor is inserted
through the vascular access device.
[0117] In an embodiment of the seventh aspect, the step of
withdrawing comprises withdrawing a blood sample through the
vascular access device.
[0118] In an embodiment of the seventh aspect, the method further
comprises displaying the calibrated sensor data.
[0119] In an embodiment of the seventh aspect, the method further
comprises coupling a blood chemistry device to the continuous
analyte sensor system.
[0120] In an embodiment of the seventh aspect, the blood chemistry
device performs the step of analyzing at least one blood sample
from the host.
[0121] In an embodiment of the seventh aspect, the blood chemistry
device performs the step of measuring a reference analyte value
from the blood sample.
[0122] In an eighth aspect, a continuous analyte sensor system is
provided, the system comprising a continuous analyte sensor
configured for insertion into a host; and a computer system
operatively connected to the continuous analyte sensor, wherein the
computer system is configured to receive analyte sensor data from
the continuous analyte sensor, the analyte sensor data comprising
at least one sensor data point and calibration information, and
wherein the computer system is configured to calibrate the analyte
sensor data from the calibration information.
[0123] In an embodiment of the eighth aspect, the analyte sensor is
a glucose sensor.
[0124] In an embodiment of the eighth aspect, the continuous
analyte sensor comprises a vascular access device configured for
communication with a vascular system of the host, and wherein the
continuous analyte sensor is configured to extend through the
vascular access device, wherein the analyte sensor is configured to
measure a concentration of an analyte within a vascular system of
the host.
[0125] In an embodiment of the eighth aspect, the vascular access
device is configured to operatively couple to a blood chemistry
analysis device for measuring a blood chemistry of the host.
[0126] In an embodiment of the eighth aspect, the blood chemistry
device is configured to withdraw a blood sample through the
vascular access device, and wherein the calibration information
comprises the blood sample or a measurement associated
therewith.
[0127] In an embodiment of the eighth aspect, the blood chemistry
device is configured to measure a reference analyte value from the
host, and wherein the calibration information comprises the
reference analyte value.
[0128] In an embodiment of the eighth aspect, the system further
comprises a device configured to automatically obtain the
calibration information, wherein the device is operatively coupled
to the sensor system.
[0129] In an embodiment of the eighth aspect, the continuous
analyte sensor comprises a vascular access device configured for
communication with a vascular system of the host, wherein the
vascular access device comprises an analyte sensor at least
partially integrally incorporated on an exterior surface the
vascular access device and further comprises sensor electronics
operatively connected to the analyte sensor, wherein the sensor
electronics are configured to measure a concentration of an analyte
within a blood stream of the host.
[0130] In an embodiment of the eighth aspect, the vascular access
device is configured to operatively couple to a blood chemistry
analysis device for measuring a blood chemistry of the host.
[0131] In an embodiment of the eighth aspect, the blood chemistry
device is configured to withdraw a blood sample through the
vascular access device, and wherein the calibration information
comprises the blood sample or a measurement associated
therewith.
[0132] In an embodiment of the eighth aspect, the blood chemistry
device is configured to measure a reference analyte value from the
host, and wherein the calibration information comprises the
reference analyte value.
[0133] In an embodiment of the eighth aspect, the system further
comprises a device configured to automatically obtain the
calibration information, wherein the device is operatively coupled
to the sensor system.
[0134] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode and a reference electrode, and
wherein at least one of the working electrode and the reference
electrode comprises a wire.
[0135] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are coaxial.
[0136] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the wires are juxtapositioned.
[0137] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode and a reference electrode, wherein
the working electrode and the reference electrode are both wires,
and wherein the reference electrode is helically wound around the
working electrode.
[0138] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode is
flexible.
[0139] In an embodiment of the eighth aspect, the analyte sensor
comprises a working electrode, and wherein the working electrode
has a variable stiffness.
[0140] In an embodiment of the eighth aspect, the analyte sensor
comprises at least one wire having a helical configuration, and
wherein a variable stiffness in the helical wire is provided by at
least one of a variable pitch of the helical wire and a variable
cross-section of the helical wire.
BRIEF DESCRIPTION OF THE DRAWINGS
[0141] 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.
[0142] FIG. 1B is a side view of the analyte sensor system of FIG.
1A, showing the protective sheath removed.
[0143] FIG. 1C1 is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0144] FIG. 1C2 is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0145] FIG. 1D is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0146] FIG. 1E is a close-up cut away view of a portion of the
analyte sensor system of FIG. 1A.
[0147] FIG. 2A is a perspective view of another embodiment of the
analyte sensor system, including a catheter with a sensor
integrally formed thereon.
[0148] FIG. 2B is a perspective view of the analyte sensor system
of FIG. 2A.
[0149] 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.
[0150] 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.
[0151] 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.
[0152] 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.
[0153] FIG. 3A is a perspective view of a first portion of one
embodiment of an analyte sensor.
[0154] FIG. 3B is a perspective view of a second portion of the
analyte sensor of FIG. 3A.
[0155] FIG. 3C is a cross section of the analyte sensor of FIG. 3B,
taken on line C-C.
[0156] FIG. 4 is a graph illustrating in vivo function of an
analyte sensor system of the embodiment shown in FIG. 1A.
[0157] FIG. 5 is a graph illustrating in vivo function of an
analyte sensor system of the embodiment shown in FIG. 1A.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0158] 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
[0159] In order to facilitate an understanding of the preferred
embodiments, a number of terms are defined below.
[0160] 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 fluid (for example, blood,
interstitial fluid, cerebral spinal fluid, lymph fluid or urine)
that can be analyzed. 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 glucose. However, other
analytes are contemplated as well, including but not limited to
acarboxyprothrombin; acylcarnitine; adenine phosphoribosyl
transferase; adenosine deaminase; albumin; alpha-fetoprotein; amino
acid profiles (arginine (Krebs cycle), histidine/urocanic acid,
homocysteine, phenylalanine/tyrosine, tryptophan);
andrenostenedione; antipyrine; arabinitol enantiomers; arginase;
benzoylecgonine (cocaine); biotinidase; biopterin; c-reactive
protein; camitine; camosinase; CD4; ceruloplasmin; chenodeoxycholic
acid; chloroquine; cholesterol; cholinesterase; conjugated 1-.beta.
hydroxy-cholic acid; cortisol; creatine kinase; creatine kinase MM
isoenzyme; cyclosporin A; d-penicillamine; de-ethylchloroquine;
dehydroepiandrosterone sulfate; DNA (acetylator polymorphism,
alcohol dehydrogenase, alpha 1-antitrypsin, cystic fibrosis,
Duchenne/Becker muscular dystrophy, 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 .beta.-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, .beta.); lysozyme;
mefloquine; netilmicin; phenobarbitone; phenytoin;
phytanic/pristanic acid; progesterone; prolactin; prolidase; purine
nucleoside phosphorylase; quinine; reverse tri-iodothyronine (rT3);
selenium; serum pancreatic lipase; sissomicin; somatomedin C;
specific antibodies (adenovirus, anti-nuclear antibody, anti-zeta
antibody, arbovirus, Aujeszky's disease virus, dengue virus,
Dracunculus medinensis, Echinococcus granulosus, Entamoeba
histolytica, enterovirus, Giardia 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).
[0161] 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.
[0162] 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.
[0163] 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
(2 e.sup.-) and one molecule of oxygen (O.sub.2), which produces
the electronic current being detected.
[0164] 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.
[0165] 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. The sensing region generally comprises a
non-conductive body, a working electrode (anode), and can include a
reference electrode (optional), and/or a counter electrode
(cathode) forming electrochemically reactive surfaces on the
body.
[0166] 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.
[0167] 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.
[0168] 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.
[0169] 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.
[0170] 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.
[0171] The terms "raw data," "raw data stream", "raw 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 comprises individual measurements taken at time intervals
ranging from fractions of a second up to, for example, 1, 2, or 5
minutes or longer. In some embodiments, the terms can refer to data
that has been integrated or averaged over a time period (e.g., 5
minutes).
[0172] 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).
[0173] 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.
[0174] 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.
[0175] 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.
[0176] 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 comprises an immobilized glucose
oxidase enzyme, which enables a reaction to occur between glucose
and oxygen whereby a concentration of glucose can be measured.
[0177] 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.
[0178] 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.
[0179] The terms "interferents" 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 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
concentration. In one example of an electrochemical sensor,
interfering species are compounds with an oxidation potential that
substantially overlaps that of the analyte to be measured, thereby
producing a false positive signal.
[0180] 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. No. 4,994,167 and U.S. Pat. No. 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.
[0181] 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 is not to be limited to a special
or customized meaning), and refers without limitation to sample of
a host body, for example blood, interstitial fluid, spinal fluid,
saliva, urine, tears, sweat, tissue, fat, and the like.
[0182] 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.
[0183] 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.
[0184] 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.
[0185] 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.
[0186] 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.
[0187] 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.
[0188] 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 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.
[0189] 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 about
3.5 to about 7.5 picoAmps of current for every 1 mg/dL of
glucose.
[0190] 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.
[0191] 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.
[0192] 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.
[0193] 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.
[0194] 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, where additional data
analysis and glucose concentration determination can occur.
[0195] 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.
[0196] 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.
[0197] 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, 1, 2, or 5 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).
[0198] 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.
[0199] 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.
[0200] 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.
[0201] 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 linke, 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).
[0202] 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 and the like.
[0203] 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.
[0204] 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,
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).
[0205] 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.
[0206] 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.
Overview
[0207] 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,
haemodynamic insufficiency, severe fluid imbalance or with the
failure of one or more of the major organ systems (life-critical
systems or others). More than 5 million people are admitted
annually to intensive care units (ICUs) and critical care units
(CCUs) in the United States.
[0208] 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 reducing costs while at the
same time reducing ICU/CCU mortality rates by improving care. 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 a host's analyte
concentration.
[0209] Hyperglycemia is a medical condition in which an excessive
amount of glucose circulates in a host. Medical studies suggest a
relationship between hyperglycemia and host outcome in
intensive/critical care settings. For example, 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.
[0210] Hyperglycemia can also be an issue in non-critical care
settings, such as in the general hospital population, such as for
diabetes hosts admitted for non-glucose-related medical conditions,
or in clinical settings, such as the doctor's office, such as
during glucose challenge tests, or treatment of the elderly or the
very young, or others who may have difficulty with glucose
control.
[0211] 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. The
preferred embodiments disclose systems and methods to reduce and/or
minimize the interaction required to regularly (e.g., continuously)
measure the host's glucose concentration.
[0212] Unfortunately it has been shown that an effort to maintain
tight control of glucose levels (e.g., about 80-129 mg/dl) can
increase the risk of hypoglycemia using conventional systems and
methods. For example, administration of insulin, quality, and
timing of meal ingestion, and the like can lead to hypoglycemia.
Because hypoglycemia can cause shock and death (immediate
problems), the clinical staff rigorously avoids it, 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.
[0213] Accordingly, 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. Therefore, there is an urgent need for
devices and methods that offer continuous, robust glucose
monitoring, to improve patient care and lower medical costs. The
preferred embodiments describe systems and methods for providing
continuous glucose monitoring while providing alarms or alerts that
aid in avoiding hypoglycemic events.
[0214] Hyperglycemia can be managed in a variety of ways.
Currently, for hosts in an intensive care setting, such as and ICU,
CCU or emergency room (ER), hyperglycemia is managed with
sliding-scale IV insulin, that stops insulin delivery at about 150
to 200 mg/dl. This generally requires monitoring by a nurse (using
a hand-held clinical glucose meter) and insulin administration at
least every six hours. Maintaining tight glucose control within the
normal range (e.g., 80-110 mg/dl) currently requires hourly or even
more frequent monitoring and insulin administration. This places an
undue burden on the nursing staff. The preferred embodiments
provide devices and methods for automated, continuous glucose
monitoring (e.g., indwelling in the circulatory system), to enable
tight glucose control.
[0215] 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. Use of an in-dwelling continuous
glucose monitor 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.
[0216] In another example, the in-dwelling continuous glucose
monitor can be used in an ER setting. In the ER, a host may be
unable to communicate with the staff. Routine use of a continuous
analyte monitor (e.g., glucose, creatinine, phosphate,
electrolytes, or drugs) can enable the ER staff to monitor and
respond to analyte concentration changes indicative of the host's
condition (e.g., the host's glucose concentration) without host
input.
[0217] 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 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 bilirubin concentration continuously monitored by an
in-dwelling continuous analyte monitor until the condition has
receded.
[0218] 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.
Applications/Uses
[0219] One aspect of the preferred embodiments provides a system
for in vivo continuous analyte monitoring (e.g., glucose, 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) 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.
[0220] FIGS. 1A to 1E illustrate one embodiment of an exemplary
analyte sensor system 10 for measuring an analyte (e.g., glucose,
urea, potassium, pH, proteins, etc.) 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). 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.
[0221] 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.
[0222] Referring now to FIGS. 1A to 1E, 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.
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.
[0223] The illustrations FIGS. 1A to 1E show one exemplary
embodiment 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.
[0224] 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.
[0225] 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.
[0226] Referring again to FIGS. 1A to 1E, 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 on an inner surface (e.g., the
lumen) or outer surface of the catheter, while in other
embodiments, the sensor is configured to "free float" within the
lumen of the catheter.
[0227] In some embodiments, the sensor 14 is configured to measure
the concentration of an analyte (e.g., glucose, 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) within the host's blood stream.
Preferably, 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. 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. publication US
2006-0020192 and/or U.S. publication US 2006-0036143, both 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.
[0228] Referring to 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.
[0229] 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). 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.
[0230] 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.
[0231] 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.
[0232] 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.
[0233] 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.
[0234] 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.
[0235] 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 (e.g., glucose, 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) 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. Various systems and methods for
design and manufacture of continuous analyte sensors are described
in more detail elsewhere herein.
[0236] 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).
[0237] 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 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.
[0238] 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.
[0239] 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.
[0240] 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
co-pending U.S. Publication No. US-2005-0143635-A1, and U.S. patent
application Ser. No. ______ filed on even date herewith and
entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR,"
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.
[0241] 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, between about 1 and 24
hours, between about 1 and 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).
[0242] 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.
[0243] 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.
[0244] 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.
[0245] 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.
[0246] 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.
[0247] 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/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.
[0248] 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.
[0249] 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.).
[0250] Preferably, the sensor is designed to include a protective
cap, as illustrated in FIGS. 1A-1E. Namely, FIG. 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.
[0251] The exemplary sensor system 10 of FIG. 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.
[0252] 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.
[0253] 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.
[0254] 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).
[0255] 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).
[0256] 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).
[0257] 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.
[0258] 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.
[0259] 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.
[0260] 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.
[0261] Generally, the sensor system is provided with a cap that
covers the catheter and in vivo portion of the integral sensor. 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.
[0262] In some embodiments, a glucose sensor system includes a
sensing mechanism substantially similar to that described in U.S.
Publication 2006-0020187, 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, 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.
[0263] 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.)
[0264] In some embodiments, a second working electrode 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, as disclosed in copending U.S. Publication
No. US-2005-0143635-A1 and co-pending U.S. patent application Ser.
No. ______ filed on even date herewith and entitled "DUAL ELECTRODE
SYSTEM FOR A CONTINUOUS ANALYTE SENSOR," herein incorporated by
reference in its entirety.
[0265] 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.
[0266] 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, 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).
[0267] 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.
[0268] 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).
[0269] 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.
Exemplary Sensor Configurations
[0270] 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 application Ser. No. 11/360,250
filed Feb. 22, 2006 and entitled "ANALYTE SENSOR," 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.
[0271] 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.
[0272] In preferred embodiments, each electrode is formed from a
fine wire with a diameter of from about 0.001 inches or less to
about 0.010 inches or more, for example, and is formed from, e.g.,
a plated insulator, a plated wire, or bulk electrically conductive
material. Although the illustrated electrode configuration and
associated text describe one preferred method of 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. No. 5,711,861 to Ward et al., U.S. Pat. No. 6,642,015 to
Vachon et al., U.S. Pat. No. 6,654,625 to Say et al., U.S. Pat. No.
6,565,509 to Say et al. , U.S. Pat. No. 6,514,718 to Heller, U.S.
Pat. No. 6,465,066 to Essenpreis et al., U.S. Pat. No. 6,214,185 to
Offenbacher et al., U.S. Pat. No. 5,310,469 to Cunningham et al.,
and U.S. Pat. No. 5,683,562 to Shaffer et al., U.S. Pat. No.
6,579,690 to Bonnecaze et al., U.S. Pat. No. 6,484,046 to Say et
al., U.S. Pat. No. 6,512,939 to Colvin et al., U.S. Pat. No.
6,424,847 to Mastrototaro et al., U.S. Pat. No. 6,424,847 to
Mastrototaro et al, for example. All of the above patents are
incorporated in their entirety herein by reference and are not
inclusive of all applicable analyte sensors; in general, it should
be understood that the disclosed embodiments are applicable to a
variety of analyte sensor configurations. 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).
[0273] 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.
[0274] 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.
[0275] 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 (2 e.sup.-) and one molecule of oxygen (O.sub.2),
which produces the electronic current being detected.
[0276] 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, polyiride, 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.
[0277] 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, 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.
[0278] 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.
[0279] 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.
[0280] 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.
[0281] 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.
[0282] 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.
[0283] 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.
[0284] 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. Publication No. US-2005-0161346-A1, U.S.
Publication No. US-2005-0143635-A1, and co-pending U.S. patent
application Ser. No. ______ filed on even date herewith and
entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS ANALYTE SENSOR"
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 comprising 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.
[0285] 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.
[0286] 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 axis. While not
wishing to be bound by theory, it is believed that a coaxial design
of the sensor enables a symmetrical design without a preferred bend
radius. Namely, in contrast to prior art sensors comprising a
substantially planar configuration that can suffer from regular
bending about the plane of the sensor, the coaxial design of the
preferred embodiments do not have a preferred bend radius and
therefore are not subject to regular bending about a particular
plane (which can cause fatigue failures and the like). However,
non-coaxial sensors can be implemented with the sensor system of
the preferred embodiments.
[0287] 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.
[0288] 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.
[0289] 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.
[0290] 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.
[0291] In addition to the embodiments described above, the sensor
can be configured with additional working electrodes as described
in U.S. Publication No. US-2005-0143635-A1, U.S. Pat. No.
7,081,195, and U.S. patent application Ser. No. ______ filed on
even date herewith and entitled "DUAL ELECTRODE SYSTEM FOR
CONTINUOUS ANALYTE SENSOR," 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.
[0292] 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.
[0293] In some alternative embodiments, the sensor is configured as
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 (without active enzyme, for
example). This second electrode provides a signal composed mostly
of the baseline signal, b.
[0294] 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.
Publication No. US-2005-0143635-A1 describes systems and methods
for subtracting the baseline from a sensor signal.
[0295] 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.
[0296] 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).
[0297] 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.
[0298] 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).
[0299] 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 0.015, 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.
Publication 2006-0016700, which is incorporated herein by reference
in its entirety.
[0300] 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.
[0301] 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.
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.
[0302] 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. Publication No.
US-2005-0245799-A1 describes biointerface and membrane system
configurations and materials that may be applied to the preferred
embodiments.
Electrode Domain
[0303] 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.
[0304] In one embodiment, the electrode domain 347 includes a
flexible, water-swellable, hydrogel film having a "dry film"
thickness of from about 0.05 micron or less to about 20 microns or
more, more preferably from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,
0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5
microns, and more preferably still from about 2, 2.5 or 3 microns
to about 3.5, 4, 4.5, or 5 microns. "Dry film" thickness refers to
the thickness of a cured film cast from a coating formulation by
standard coating techniques.
[0305] 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 non-ionic hydrophilic polyether segments, wherein the
polyurethane polymer is crosslinked with a water-soluble
carbodiimide (e.g., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
(EDC)) in the presence of polyvinylpyrnolidone and cured at a
moderate temperature of about 50.degree. C.
[0306] In some preferred embodiments, the electrode domain 347 is
formed from a hydrophilic polymer such as polyvinylpyrrolidone
(PVP). An electrode domain formed from PVP has been shown to reduce
break-in time of analyte sensors; for example, a glucose sensor
utilizing a cellulosic-based interference domain such as described
in more detail below.
[0307] Preferably, the electrode domain is deposited by vapor
deposition, spray coating, dip coating, or other thin film
techniques on the electroactive surfaces of the sensor. In one
preferred embodiment, the electrode domain is formed by dip-coating
the electroactive surfaces in an electrode layer solution and
curing the domain for a time of from about 15 minutes to about 30
minutes at a temperature of from about 40.degree. C. to about
55.degree. C. (and can be accomplished under vacuum (e.g., 20 to 30
mmHg)). In embodiments wherein dip-coating is used to deposit the
electrode domain, a preferred insertion rate of from about 1 to
about 3 inches per minute into the electrode layer solution, with a
preferred dwell time of from about 0.5 to about 2 minutes in the
electrode layer solution, and a preferred withdrawal rate of from
about 0.25 to about 2 inches per minute from the electrode layer
solution provide a functional coating. However, values outside of
those set forth above can be acceptable or even desirable in
certain embodiments, for example, depending upon solution viscosity
and solution surface tension, as is appreciated by one skilled in
the art. In one embodiment, the electroactive surfaces of the
electrode system are dip-coated one time (one layer) and cured at
50.degree. C. under vacuum for 20 minutes.
[0308] 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.
Interference Domain
[0309] Interferents are molecules or other species that are reduced
or oxidized at the electrochemically reactive surfaces of the
sensor, either directly or via an electron transfer agent, to
produce a false positive analyte signal. In preferred embodiments,
an interference domain 348 is provided that substantially
restricts, resists, or blocks the flow of one or more interfering
species. Some known interfering species for a glucose sensor, as
described in more detail above, include acetaminophen, ascorbic
acid, bilirubin, cholesterol, creatinine, dopamine, ephedrine,
ibuprofen, L-dopa, 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
analyte, e.g., glucose.
[0310] In one embodiment, the interference domain 348 is formed
from one or more cellulosic derivatives. In general, cellulosic
derivatives include polymers such as cellulose acetate, cellulose
acetate butyrate, 2-hydroxyethyl cellulose, cellulose acetate
phthalate, cellulose acetate propionate, cellulose acetate
trimellitate, and the like.
[0311] 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. Additionally, a casting solution or dispersion of
cellulose acetate butyrate at a weight percent of about 15% to
about 25%, preferably from about 15%, 16%, 17%, 18%, 19% to about
20%, 21%, 22%, 23%, 24% or 25%, and more preferably about 18% is
preferred. Preferably, the casting solution includes a solvent or
solvent system, for example an acetone:ethanol solvent system.
Higher or lower concentrations can be preferred in certain
embodiments. A plurality of layers of cellulose acetate butyrate
can be advantageously combined to form the interference domain in
some embodiments, for example, three layers can be employed. It can
be desirable to employ a mixture of cellulose acetate butyrate
components with different molecular weights in a single solution,
or to deposit multiple layers of cellulose acetate butyrate from
different solutions comprising cellulose acetate butyrate of
different molecular weights, different concentrations, and/or
different chemistries (e.g., functional groups). It can also be
desirable to include additional substances in the casting solutions
or dispersions, e.g., functionalizing agents, crosslinking agents,
other polymeric substances, substances capable of modifying the
hydrophilicity/hydrophobicity of the resulting layer, and the
like.
[0312] 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. 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.
[0313] Layer(s) prepared from combinations of cellulose acetate and
cellulose acetate butyrate, or combinations of layer(s) of
cellulose acetate and layer(s) of cellulose acetate butyrate can
also be employed to form the interference domain 348.
[0314] In some alternative embodiments, additional polymers, such
as Nafione, can be used in combination with cellulosic derivatives
to provide equivalent and/or enhanced function of the interference
domain 348. As one example, a 5 wt % Nafion.RTM. casting solution
or dispersion can be used in combination with a 8 wt % cellulose
acetate casting solution or dispersion, e.g., by dip coating at
least one layer of cellulose acetate and subsequently dip coating
at least one layer Nafion.RTM. onto a needle-type sensor such as
described with reference to the preferred embodiments. Any number
of coatings or layers formed in any order may be suitable for
forming the interference domain of the preferred embodiments.
[0315] 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 (or other
polymer) prior to film formation thereon. In preferred embodiments,
acetone and ethanol are used as solvents for cellulose acetate;
however one skilled in the art appreciates the numerous solvents
that are suitable for use with cellulosic derivatives (and other
polymers). Additionally, one skilled in the art appreciates that
the preferred relative amounts of solvent can be dependent upon the
cellulosic derivative (or other polymer) used, its molecular
weight, its method of deposition, its desired thickness, and the
like. However, a percent solute of from about 1% to about 25% is
preferably used to form the interference domain solution so as to
yield an interference domain having the desired properties. The
cellulosic derivative (or other polymer) used, its molecular
weight, method of deposition, and desired thickness can be
adjusted, depending upon one or more other of the parameters, and
can be varied accordingly as is appreciated by one skilled in the
art.
[0316] 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 low molecular weight species. The interference domain 348 is
permeable to relatively low molecular weight substances, such as
hydrogen peroxide, but restricts the passage of higher molecular
weight substances, including glucose and ascorbic acid. Other
systems and methods for reducing or eliminating interference
species that can be applied to the membrane system of the preferred
embodiments are described in U.S. Publication No.
US-2005-0115832-A1, U.S. Publication No. US-2005-0176136-A1, U.S.
Publication No. US-2005-0161346-A1, and U.S. Publication No.
US-2005-0143635-A1, U.S. Publication No. US-2006-0020187-A1, and
co-pending U.S. patent application Ser. No. ______ filed on even
date herewith and entitled "DUAL ELECTRODE SYSTEM FOR A CONTINUOUS
ANALYTE SENSOR," all of which are incorporated herein by reference
in their entirety. In some alternative embodiments, a distinct
interference domain is not included.
[0317] In preferred embodiments, the interference domain 348 is
deposited directly onto the electroactive surfaces of the sensor
for a domain thickness of from about 0.05 micron or less to about
20 microns or more, more preferably from about 0.05, 0.1, 0.15,
0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5
microns to about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, or 19.5 microns, and more preferably still from about 1,
1.5 or 2 microns to about 2.5 or 3 microns. Thicker membranes can
also be desirable in certain embodiments, but thinner membranes are
generally preferred because they can have a lower impact on the
rate of diffusion of hydrogen peroxide from the enzyme membrane to
the electrodes.
[0318] In general, the membrane systems of the preferred
embodiments can be formed and/or deposited on the exposed
electroactive surfaces (e.g., one or more of the working and
reference electrodes) using known thin film techniques (for
example, casting, spray coating, drawing down, electro-depositing,
dip coating, and the like), however casting or other known
application techniques can also be utilized. Preferably, the
interference domain is deposited by vapor deposition, spray
coating, or dip coating. In one exemplary embodiment of a
needle-type (transcutaneous) sensor such as described herein, the
interference domain is formed by dip coating the sensor into an
interference domain solution using an insertion rate of from about
20 inches/min to about 60 inches/min, preferably 40 inches/min, a
dwell time of from about 0 minute to about 5 seconds, preferably 0
seconds, and a withdrawal rate of from about 20 inches/minute to
about 60 inches/minute, preferably about 40 inches/minute, and
curing (drying) the domain from about 1 minute to about 30 minutes,
preferably from about 3 minutes to about 15 minutes (and can be
accomplished at room temperature or under vacuum (e.g., 20 to 30
mmHg)). In one exemplary embodiment including cellulose acetate
butyrate interference domain, a 3-minute cure (i.e., dry) time is
preferred between each layer applied. In another exemplary
embodiment employing a cellulose acetate interference domain, a 15
minute cure (i.e., dry) time is preferred between each layer
applied.
[0319] The dip process can be repeated at least one time and up to
10 times or more. The preferred number of repeated dip processes
depends upon the cellulosic derivative(s) used, their
concentration, conditions during deposition (e.g., dipping) and the
desired thickness (e.g., sufficient thickness to provide functional
blocking of (or resistance to) certain interferents), and the like.
In some embodiments, 1 to 3 microns may be preferred for the
interference domain thickness; however, values outside of these can
be acceptable or even desirable in certain embodiments, for
example, depending upon viscosity and surface tension, as is
appreciated by one skilled in the art. In one exemplary embodiment,
an interference domain is formed from three layers of cellulose
acetate butyrate. In another exemplary embodiment, an interference
domain is formed from 10 layers of cellulose acetate. In
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.
[0320] 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.
Enzyme Domain
[0321] 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.
[0322] 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. Publication No. US-2005-0054909-A1.
[0323] In preferred embodiments, the enzyme domain is deposited
onto the interference domain for a domain thickness of from about
0.05 micron or less to about 20 microns or more, more preferably
from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5,
1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5 microns, and more
preferably still from about 2, 2.5 or 3 microns to about 3.5, 4,
4.5, or 5 microns. However in some embodiments, the enzyme domain
can be deposited directly onto the electroactive surfaces.
Preferably, the enzyme domain is deposited by spray or dip coating.
In one embodiment of needle-type (transcutaneous) sensor such as
described herein, the enzyme domain is formed by dip coating the
interference domain coated sensor into an enzyme domain solution
and curing the domain for from about 15 to about 30 minutes at a
temperature of from about 40.degree. C. to about 55.degree. C. (and
can be accomplished under vacuum (e.g., 20 to 30 mmHg)). In
embodiments wherein dip coating is used to deposit the enzyme
domain at room temperature, a preferred insertion rate of from
about 0.25 inch per minute to about 3 inches per minute, with a
preferred dwell time of from about 0.5 minutes to about 2 minutes,
and a preferred withdrawal rate of from about 0.25 inch per minute
to about 2 inches per minute provides a functional coating.
However, values outside of those set forth above can be acceptable
or even desirable in certain embodiments, for example, depending
upon viscosity and surface tension, as is appreciated by one
skilled in the art. In one embodiment, the enzyme domain is formed
by dip coating two times (namely, forming two layers) in an enzyme
domain solution and curing at 50.degree. C. under vacuum for 20
minutes. However, in some embodiments, the enzyme domain can be
formed by dip coating and/or spray coating one or more layers at a
predetermined concentration of the coating solution, insertion
rate, dwell time, withdrawal rate, and/or desired thickness.
Resistance Domain
[0324] 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.
[0325] 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.
[0326] 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)).
[0327] In alternative embodiments, a lower ratio of
oxygen-to-glucose can be sufficient to provide excess oxygen by
using a high oxygen solubility domain (for example, a silicone or
fluorocarbon-based material or domain) to enhance the
supply/transport of oxygen to the enzyme domain. If more oxygen is
supplied to the enzyme, then more glucose can also be supplied to
the enzyme without creating an oxygen rate-limiting excess. In
alternative embodiments, the resistance domain is formed from a
silicone composition, such as is described in U.S. Publication No.
US-2005-0090607-A1.
[0328] 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.
[0329] 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.
[0330] In some embodiments, the resistance domain is formed from a
silicone polymer modified to allow analyte (e.g., glucose)
transport.
[0331] 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.. Co-pending
U.S. patent application Ser. No. 11/404,417 and entitled, "SILICONE
BASED MEMBRANES FOR USE IN IMPLANTABLE GLUCOSE SENSORS," 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.
[0332] 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.
[0333] 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.
[0334] 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.
[0335] 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.
[0336] 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.
[0337] 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.
[0338] In one embodiment, the resistance domain is formed by spray
coating at least six layers (namely, rotating the sensor seventeen
times by 1200 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.
[0339] 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.
[0340] 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. 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.
Treatment of Interference Domain/Membrane System
[0341] 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.
[0342] 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.
[0343] 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.
[0344] In embodiments wherein electron beam radiation is used to
treat the membrane system (or interference domain), a preferred
exposure time is from about 6 k 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.
[0345] 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.
[0346] 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.
[0347] 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.
Therapeutic Agents
[0348] 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.
[0349] In one embodiment, heparin is incorporated into the analyte
sensor system. In a further embodiment, heparin is coated on the
catheter and/or sensor 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.
[0350] 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.
[0351] 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.
[0352] 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.
[0353] 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.
[0354] 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).
[0355] 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.
[0356] 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.
[0357] 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.
[0358] 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.
[0359] 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.
Release of Bioactive Agents
[0360] 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.
[0361] 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.
[0362] 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.
Loading of Bioactive Agents
[0363] 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.
[0364] 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. %.
[0365] 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.
[0366] Referring now to microencapsulated bioactive agents, the
release of the agents from these polymeric systems generally occur
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.
[0367] 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.
Sensor Electronics
[0368] 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.
[0369] 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.
[0370] 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.
[0371] 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.
[0372] 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.
[0373] 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. 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.
[0374] In some embodiments, the processor module comprises a
digital filter, 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.
[0375] In some embodiments, the processor module is configured 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).
[0376] 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.)
[0377] In some embodiments, the processor further performs 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.
[0378] 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.
[0379] 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. 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.
[0380] 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.
[0381] 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.
[0382] 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.
Algorithms
[0383] 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).
[0384] 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), 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.
[0385] 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.
[0386] 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).
[0387] 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.
[0388] 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.
[0389] In some embodiments, a data matching module, also referred
to as the processor module, 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.
[0390] In some embodiments, a calibration set module, also referred
to as the calibration module or processor module, forms 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.
[0391] In some embodiments, a conversion function module, also
referred to as the conversion module or processor module, uses 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.
[0392] 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.
[0393] 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.
[0394] 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.
Publication No. US-2005-0143635-A1 describes systems and methods
for subtracting the baseline from a sensor signal.
[0395] 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.
[0396] In some alternative embodiments, a regression equation
y=mx+b is used 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.)
[0397] 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).
[0398] 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.
[0399] In some embodiments, a sensor data transformation module,
also referred to as the calibration module, conversion module, or
processor module, uses 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 = ( rawvalue - offset ) slope ##EQU00001##
[0400] In some embodiments, an output module provides 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.
[0401] 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.
[0402] 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 measurement
for use in calibrating the sensor. Furthermore, baseline and/or
sensitivity measurements 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. Publication No.
US-2005-0143635-A1.
[0403] 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 D5W--a 5%
dextrose solution). In one embodiment, a known volume of D5W 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.
[0404] 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.
[0405] 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).
[0406] 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.
[0407] In another embodiment of sensor calibration (and/or
re-calibration) during use, a calibration solution (e.g., 40 mg/dL
equivalent glucose, D540 or D5W) 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.
EXAMPLES
Example 1
Glucose Sensor System Trial in Dogs
[0408] 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."
[0409] 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 (comprising
BAYHYDROL.RTM. 123, an aliphatic polycarbonate urethane resin) and
drying. An enzyme domain was formed over the electrode domain by
subsequently dip coating the assembly in an enzyme solution
(comprising BAYHYDROL.RTM. 140AQ, an aliphatic polyester urethane
resin, and glucose oxidase) and drying. A resistance domain was
formed over the enzyme domain by spraying the resistance domain
solution (comprising a blend of CHRONOTHANE.RTM.-1020 (a
polyetherurethaneurea based on polytetramethylene glycol, methylene
diisocyanate and organic amines) and CHRONOTHANE.RTM.-H (a
polyetherurethaneurea based on polytetramethylene glycol,
polyethylene glycol, methylene diisocyanate, and organic amines))
on the sensor construct.
[0410] After the sensor was constructed, it was placed in the
protective sheath and then threaded through and attached to the
fluid coupler.
[0411] 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.
[0412] Prior to use, the sensors were sterilized using electron
beam.
[0413] 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. Publ. 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.
[0414] 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-axis, glucose concentrations
for the "SMBG" controls are shown on the right-hand y-axis, and
time is shown on the X-axis. Each time interval on the X-axis
represents 29-minutes (e.g., 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
[0415] 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-axis, glucose concentrations for the
"SMBG" controls are shown on the right-hand y-axis, and time is
shown on the X-axis. 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.
[0416] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Pat. No. 4,994,167; U.S. Pat. No. 4,757,022; U.S. Pat. No.
6,001,067; U.S. Pat. No. 6,741,877; U.S. Pat. No. 6,702,857; U.S.
Pat. No. 6,558,321; U.S. Pat. No. 6,931,327; U.S. Pat. No.
6,862,465; U.S. Pat. No. 7,074,307; U.S. Pat. No. 7,081,195; U.S.
Pat. No. 7,108,778; and U.S. Pat. No. 7,110,803.
[0417] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
Publication No. US-2005-0176136-A1; U.S. Publication No.
US-2005-0251083-A1; U.S. Publication No. US-2005-0143635-A1; U.S.
Publication No. US-2005-0181012-A1; U.S. Publication No.
US-2005-0177036-A1; U.S. Publication No. US-2005-0124873-A1; U.S.
Publication No. US-2005-0115832-A1; U.S. Publication No.
US-2005-0245799-A1; U.S. Publication No. US-2005-0245795-A1; U.S.
Publication No. US-2005-0242479-A1; U.S. Publication No.
US-2005-0182451-A1; U.S. Publication No. US-2005-0056552-A1; U.S.
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US-2005-0154271-A1; U.S. Publication No. US-2004-0199059-A1; U.S.
Publication No. US-2005-0054909-A1; U.S. Publication No.
US-2005-0112169-A1; U.S. Publication No. US-2005-0051427-A1; U.S.
Publication No. US-2003-0032874-A1; U.S. Publication No.
US-2005-0103625-A1; U.S. Publication No. US-2005-0203360-A1; U.S.
Publication No. US-2005-0090607-A1; U.S. Publication No.
US-2005-0187720-A1; U.S. Publication No. US-2005-0161346-A1; U.S.
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US-2005-0043598-A1; U.S. Publication No. US-2003-0217966-A1; U.S.
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US-2005-0031689-A1; U.S. Publication No. US-2004-0186362-A1; U.S.
Publication No. US-2005-0027463-A1; U.S. Publication No.
US-2005-0027181-A1; U.S. Publication No. US-2005-0027180-A1; U.S.
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US-2006-0036142-A1; U.S. Publication No. US-2006-0020192-A1; U.S.
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US-2006-0036140-A1; U.S. Publication No. US-2006-0019327-A1; U.S.
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US-2006-0020189-A1; U.S. Publication No. US-2006-0036139-A1; U.S.
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US-2006-0020188-A1; U.S. Publication No. US-2006-0036141-A1; U.S.
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US-2006-0036145-A1; U.S. Publication No. US-2006-0036144-A1; U.S.
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US-2006-0040402-A1; U.S. Publication No. US-2006-0036142-A1; U.S.
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US-2006-0036143-A1; U.S. Publication No. US-2006-0036140-A1; U.S.
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US-2006-0142651-A1; U.S. Publication No. US-2006-0036145-A1; U.S.
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US-2006-0200022-A1; U.S. Publication No. US-2006-0198864-A1; U.S.
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US-2006-0189856-A1; U.S. Publication No. US-2006-0200020-A1; U.S.
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US-2006-0183984-A1; U.S. Publication No. US-2006-0183985-A1; and
U.S. Publication No. US-2006-0195029-A1.
[0418] Methods and devices that are suitable for use in conjunction
with aspects of the preferred embodiments are disclosed in U.S.
application Ser. No. 09/447,227 filed Nov. 22, 1999 and entitled
"DEVICE AND METHOD FOR DETERMINING ANALYTE LEVELS"; U.S.
application Ser. No. 11/335,879 filed Jan. 18, 2006 and entitled
"CELLULOSIC-BASED INTERFERENCE DOMAIN FOR AN ANALYTE SENSOR"; U.S.
application Ser. No. 11/334,876 filed Jan. 18, 2006 and entitled
"TRANSCUTANEOUS ANALYTE SENSOR"; U.S. application Ser. No.
11/498,410 filed Aug. 2, 2006 and entitled "SYSTEMS AND METHODS FOR
REPLACING SIGNAL ARTIFACTS IN A GLUCOSE SENSOR DATA STREAM"; U.S.
application Ser. No. 11/515,443 filed Sep. 1, 2006 and entitled
"SYSTEMS AND METHODS FOR PROCESSING ANALYTE SENSOR DATA"; U.S.
application Ser. No. 11/503,367 filed Aug. 10, 2006 and entitled
"ANALYTE SENSOR"; and U.S. application Ser. No. 11/515,342 filed
Sep. 1, 2006 and entitled "SYSTEMS AND METHODS FOR PROCESSING
ANALYTE SENSOR DATA".
[0419] 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.
[0420] 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.
[0421] 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.
[0422] 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.
* * * * *