U.S. patent application number 13/594734 was filed with the patent office on 2013-02-28 for polymer membranes for continuous analyte sensors.
This patent application is currently assigned to DEXCOM, INC.. The applicant listed for this patent is Robert J. Boock, Chris W. Dring, Jonathan Hughes. Invention is credited to Robert J. Boock, Chris W. Dring, Jonathan Hughes.
Application Number | 20130053666 13/594734 |
Document ID | / |
Family ID | 47744647 |
Filed Date | 2013-02-28 |
United States Patent
Application |
20130053666 |
Kind Code |
A1 |
Hughes; Jonathan ; et
al. |
February 28, 2013 |
POLYMER MEMBRANES FOR CONTINUOUS ANALYTE SENSORS
Abstract
Devices and methods are described for providing continuous
measurement of an analyte concentration. In some embodiments, the
devices include a membrane that has an interference domain designed
to reduce the permeation of one or more interferents.
Inventors: |
Hughes; Jonathan; (Carlsbad,
CA) ; Boock; Robert J.; (Carlsbad, CA) ;
Dring; Chris W.; (Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hughes; Jonathan
Boock; Robert J.
Dring; Chris W. |
Carlsbad
Carlsbad
Fremont |
CA
CA
CA |
US
US
US |
|
|
Assignee: |
DEXCOM, INC.
San Diego
CA
|
Family ID: |
47744647 |
Appl. No.: |
13/594734 |
Filed: |
August 24, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13594602 |
Aug 24, 2012 |
|
|
|
13594734 |
|
|
|
|
61527856 |
Aug 26, 2011 |
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Current U.S.
Class: |
600/347 ;
427/2.12 |
Current CPC
Class: |
A61B 5/14865 20130101;
G01N 27/333 20130101; A61B 5/6846 20130101; G01N 27/3271 20130101;
A61B 5/14532 20130101; C12Q 1/00 20130101; A61B 5/686 20130101;
A61B 5/14503 20130101; A61B 5/1486 20130101; A61B 2562/125
20130101 |
Class at
Publication: |
600/347 ;
427/2.12 |
International
Class: |
A61B 5/1473 20060101
A61B005/1473; B05D 7/00 20060101 B05D007/00 |
Claims
1. A method for forming a membrane on an implantable device
configured for continuous measurement of an analyte concentration,
comprising: applying a first solution to an implantable sensor or a
layer deposited thereon, the first solution having a first pH and
comprising polycations; drying the first solution to form a
polycationic layer; applying a second solution to the polycationic
layer, the second solution having a second pH and comprising
polyanions; and drying the second solution to form a polyanionic
layer.
2. The method of claim 1, wherein the first pH is approximately the
pK.sub.b of the polycations.
3. The method of claim 1, wherein the first pH is from about 9 to
10.
4. The method of claim 1, wherein the second pH is approximately
the pK.sub.a of the polyanions.
5. The method of claim 1, wherein the pH is from about 2 to 3.
6. The method of claim 1, further comprising applying a solution
comprising an enzyme onto at least one of a polycationic layer or a
polyanionic layer to form an enzyme layer.
7. The method of claim 5, wherein the analyte is glucose, and
wherein the enzyme is glucose oxidase.
8. An implantable device for continuous measurement of glucose
concentration, the device comprising: an electrode configured to
generate a signal indicative of a concentration of glucose in a
host; and a membrane located over the electrode, the membrane
comprising: a first domain that comprises an enzyme configured to
react with glucose; a second domain configured to reduce passage
therethrough of an interferent, the second domain comprising a
plurality of alternating polyelectrolyte layers, wherein the
plurality of alternating polyelectrolyte layers comprise at least
one of a polycationic layer and a polyanionic layer.
9. The implantable device of claim 8, wherein the second domain
comprises an odd number of alternating polyelectrolyte layers.
10. The implantable device of claim 8, wherein the second domain
comprises a plurality of polycationic layers, and wherein the
polycationic layers form the most distal layer and the most
proximal layer of the second domain.
11. The implantable device of claim 8, wherein the second domain
comprises at least three alternating polyelectrolyte layers.
12. The implantable device of claim 11, wherein the first and third
most distal layers with respect to the electrode are polycationic
layers, and the second most distal layer with respect to the
electrode is a polyanionic layer.
13. The implantable device of claim 8, wherein the second domain
comprises at least five alternating polyelectrolyte layers.
14. The implantable device of claim 13, wherein the first, third,
and fifth most distal layers with respect to the electrode are
polycationic layers, and the second and fourth most distal layers
with respect to the electrode are polyanionic layers.
15. The implantable device of claim 8, wherein the second domain
comprises at least seven alternating polyelectrolyte layers.
16. The implantable device of claim 15, wherein the first, third,
fifth, and seventh most distal layers with respect to the electrode
are polycationic layers, and the second, fourth, and sixth most
distal layers with respect to the sensor are polyanionic
layers.
17. The implantable device of claim 8, wherein the first domain is
distal to the second domain with respect to the electrode.
18. The implantable device of claim 8, wherein the electrode
comprises an electroactive surface.
19. The implantable device of claim 18, wherein the second domain
contacts the electroactive surface.
20. The implantable device of claim 8, wherein the polycationic
layer comprises a polycation with an average linear charge density
from about 2 to 10 e/.ANG., and wherein the polyanionic layer
comprises a polyanion with an average linear charge density from
about 2 to 10 e/.ANG..
21. The implantable device of claim 8, wherein the polycationic
layer comprises a polycation with an average linear charge density
from about 2 to 3 e/.ANG., and wherein the polyanionic layer
comprises a polyanion with an average linear charge density from
about 2 to 3 e/.ANG..
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/594,602, filed Aug. 24, 2012, which claims the benefit of
priority under 35 U.S.C. .sctn.119(e) of U.S. Provisional
Application No. 61/527,856 filed Aug. 26, 2011, the disclosure of
which is hereby expressly incorporated by reference in its entirety
and is hereby expressly made a portion of this application.
FIELD OF THE INVENTION
[0002] Devices and methods are described for providing continuous
measurement of an analyte concentration. In some embodiments, the
device has an interference domain that reduces permeation of one or
more interferents into an electrochemically reactive surface. The
interference domain can be configured to be more permeable or less
permeable to one or more interferents than to a measured analyte
species.
BACKGROUND OF THE INVENTION
[0003] Electrochemical sensors are useful in chemistry and medicine
to determine the presence or concentration of a biological analyte.
Such sensors are useful, for example, to monitor glucose in
diabetic patients and lactate during critical care events. A
variety of intravascular, transcutaneous and implantable sensors
have been developed for continuously detecting and quantifying
blood glucose values. Many implantable glucose sensors suffer from
complications within the body and provide only short-term or
less-than-accurate sensing of blood glucose. Similarly, many
transcutaneous and intravascular sensors have problems in
accurately sensing and reporting back glucose values continuously
over extended periods of time, for example, due to noise on the
signal caused by interfering species or unknown noise-causing
events.
SUMMARY OF THE INVENTION
[0004] In the first aspect, an implantable device is provided for
continuous measurement of an analyte concentration, the implantable
device comprising: a sensor configured to generate a signal
indicative of a concentration of an analyte in a host; and a
membrane located over the sensor, the membrane comprising a first
domain configured to reduce a flux therethrough of the analyte, a
second domain that comprises an enzyme, and a third domain
configured to reduce passage therethrough of an interferent, the
third domain comprising a plurality of alternating polyelectrolyte
layers.
[0005] In an embodiment of the first aspect, the plurality of
alternating polyelectrolyte layers of the third domain comprises
two types of layers. In some embodiments, the two types of layers
comprise a polycationic layer and a polyanionic layer. In some
embodiments, the polycationic layers form the most distal and the
most proximal layers of the third domain. In some embodiments, the
third domain comprises an odd number of alternating polyelectrolyte
layers. In some embodiments, the third domain comprises at least
three alternating polyelectrolyte layers. In some embodiments, the
first and third most distal layers with respect to the sensor are
polycationic layers, and the second most distal layer with respect
to the sensor is a polyanionic layer. In some embodiments, the
third domain comprises at least five alternating layers. In some
embodiments, the first, third, and fifth most distal layers with
respect to the sensor are polycationic layers, and the second and
fourth most distal layers with respect to the sensor are
polyanionic layers. In some embodiments, the third domain comprises
at least seven alternating polyelectrolyte layers. In some
embodiments, the first, third, fifth, and seventh most distal
layers with respect to the sensor are polycationic layers, and the
second, fourth, and sixth most distal layers with respect to the
sensor are polyanionic layers. In some embodiments, the two types
of layers comprise a first layer type configured to selectively
reduce passage therethrough of a first interferent and a second
layer type configured to selectively reduce passage therethrough of
a second interferent.
[0006] In an embodiment of the first aspect, the plurality of
alternating polyelectrolyte layers comprises at least three types
of layers. In some embodiments, the at least three types of layers
comprise a first layer or bilayer type configured to selectively
reduce passage therethrough of a first interferent, a second layer
bilayer type configured to selectively reduce passage therethrough
of a second interferent, and a third layer bilayer type configured
to selectively reduce passage therethrough of a third
interferent.
[0007] In an embodiment of the first aspect, the first domain is
proximal to the second domain with respect to the sensor, and
wherein the second domain is proximal to the third domain with
respect to the sensor.
[0008] In an embodiment of the first aspect, the sensor comprises
an electroactive surface.
[0009] In a second aspect, an implantable device is provided for
continuous measurement of an analyte concentration, the implantable
device comprising: a sensor configured to generate a signal
indicative of a concentration of an analyte in a host; and a
membrane located over the sensor, the membrane comprising a first
domain configured to reduce a flux therethrough of the analyte, a
second domain that comprises an enzyme, and a third domain
configured to reduce passage therethrough of an interferent, the
third domain comprising an self-assembled, ordered structure formed
from a plurality of alternating polyelectrolyte layers.
[0010] In an embodiment of the second aspect, the plurality of
layers is formed of an acetylene-based polymer.
[0011] In an embodiment of the second aspect, the plurality of
layers is cross-linked.
[0012] In an embodiment of the second aspect, the plurality of
alternating polyelectrolyte layers comprises a polycationic layer
and a polyanionic layer. In some embodiments, the polycationic
layer is configured to selectively reduce passage therethrough of a
first interferent and the polyanionic layer is configured to
selectively reduce passage therethrough of a second interferent. In
some embodiments, the polycationic layers form the most distal and
the most proximal layers of the third domain. In some embodiments,
the third domain comprises an odd number of alternating
polyelectrolyte layers. In some embodiments, the third domain
comprises at least three alternating layers. In some embodiments,
the first and third most distal layers with respect to the sensor
are polycationic layers, and the second most distal layer with
respect to the sensor is a polyanionic layer. In some embodiments,
the third domain comprises at least five alternating
polyelectrolyte layers. In some embodiments, the first, third, and
fifth most distal layers with respect to the sensor are
polycationic layers, and the second and fourth most distal layers
with respect to the sensor are polyanionic layers. In some
embodiments, the third domain comprises at least seven alternating
polyelectrolyte layers. In some embodiments, the first, third,
fifth, and seventh most distal layers with respect to the sensor
are polycationic layers, and the second, fourth, and sixth most
distal layers with respect to the sensor are polyanionic
layers.
[0013] In an embodiment of the second aspect, the third domain has
an interferent-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.8 to about zero.
[0014] In an embodiment of the second aspect, the third domain has
an interferent-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.6 to about zero.
[0015] In an embodiment of the second aspect, the third domain has
an interferent-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.3 to about zero.
[0016] In an embodiment of the second aspect, the third domain has
a thickness of from about 10 microns to about 10 nanometers.
[0017] In an embodiment of the second aspect, the third domain has
a thickness of from about 500 nanometers to about 200
nanometers.
[0018] In a third aspect, a device for continuous measurement of
glucose concentration is provided, the device comprising: an
electrode configured to generate a signal indicative of a
concentration of glucose in a host; and a membrane located over the
electrode, the membrane comprising: a first domain that comprises
an enzyme configured to react with glucose; a second domain
configured to reduce passage therethrough of an interferent, the
second domain comprising polyelectrolytes, whereby an equivalent
peak glucose response to a 1,000 mg dose of the interferent
administered to a host is less than about 100 mg/dL.
[0019] In an embodiment of the third aspect, the equivalent peak
glucose response to a 1,000 mg dose of the interferent administered
to a host is less than about 50 mg/dL.
[0020] In an embodiment of the third aspect, the equivalent peak
glucose response to a 1,000 mg dose of the interferent administered
to a host is less than about 25 mg/dL.
[0021] In an embodiment of the third aspect, the interferent can be
acetaminophen.
[0022] In an embodiment of the third aspect, the interferent can be
uric acid.
[0023] In an embodiment of the third aspect, the interferent can be
ascorbic acid.
[0024] In an embodiment of the third aspect, the interferent is
acetaminophen, and the second domain has an
acetaminophen-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.8 to about zero.
[0025] In an embodiment of the third aspect, the interferent is
acetaminophen, and the second domain has an
acetaminophen-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.6 to about zero.
[0026] In an embodiment of the third aspect, the interferent is
acetaminophen, and the second domain has an
acetaminophen-to-H.sub.2O.sub.2 sensitivity ratio of less than
about 0.3 to about zero.
[0027] In an embodiment of the third aspect, the interferent is
uric acid, and the second domain has a uric acid-to-H.sub.2O.sub.2
sensitivity ratio of less than about 0.8 to about zero.
[0028] In an embodiment of the third aspect, the interferent is
uric acid, and the second domain has a uric acid-to-H.sub.2O.sub.2
sensitivity ratio of less than about 0.6 to about zero.
[0029] In an embodiment of the third aspect, the interferent is
uric acid, and the second domain has a uric acid-to-H.sub.2O.sub.2
sensitivity ratio of less than about 0.3 to about zero.
[0030] In an embodiment of the third aspect, the interferent is
ascorbic acid, and the second domain has an ascorbic
acid-to-H.sub.2O.sub.2 sensitivity ratio of less than 0.8 to about
zero.
[0031] In an embodiment of the third aspect, the interferent is
ascorbic acid, and the second domain has an ascorbic
acid-to-H.sub.2O.sub.2 sensitivity ratio of less than about 0.6 to
about zero.
[0032] In an embodiment of the third aspect, the interferent is
ascorbic acid, and the second domain has an ascorbic
acid-to-H.sub.2O.sub.2 sensitivity ratio of less than about 0.3 to
about zero.
[0033] In an embodiment of the third aspect, the second domain
comprises a plurality of alternating polycationic and polyanionic
layers.
[0034] In a fourth aspect, a method is provided for forming a
membrane on an implantable device configured for continuous
measurement of an analyte concentration, comprising: applying a
first solution to an implantable sensor or a layer deposited
thereon, the first solution having a first pH and comprising
polycations; drying the first solution to form a polycationic
layer; applying a second solution to the polycationic layer, the
second solution having a second pH and comprising polyanions; and
drying the second solution to form a polyanionic layer.
[0035] In an embodiment of the fourth aspect, the first pH is
approximately the pK.sub.b of the polycations.
[0036] In an embodiment of the fourth aspect, the first pH is from
about 9 to 10.
[0037] In an embodiment of the fourth aspect, the second pH is
approximately the pK.sub.a of the polyanions.
[0038] In an embodiment of the fourth aspect, the pH is from about
2 to 3.
[0039] In an embodiment of the fourth aspect, the method further
comprises applying a solution comprising an enzyme onto at least
one of a polycationic layer or a polyanionic layer to form an
enzyme layer. In some embodiments, the analyte is glucose, and the
enzyme is glucose oxidase.
[0040] In a fifth aspect, an implantable device is provided for
continuous measurement of glucose concentration, the device
comprising: an electrode configured to generate a signal indicative
of a concentration of glucose in a host; and a membrane located
over the electrode, the membrane comprising: a first domain that
comprises an enzyme configured to react with glucose; and a second
domain configured to reduce passage therethrough of an interferent,
the second domain comprising a plurality of alternating
polyelectrolyte layers, wherein the plurality of alternating
polyelectrolyte layers comprise at least one of a polycationic
layer and a polyanionic layer.
[0041] In an embodiment of the fifth aspect, the second domain
comprises an odd number of alternating polyelectrolyte layers.
[0042] In an embodiment of the sixth aspect, the second domain
comprises a plurality of polycationic layers, and wherein the
polycationic layers form the most distal layer and the most
proximal layer of the second domain.
[0043] In an embodiment of the fifth aspect, the second domain
comprises at least three alternating polyelectrolyte layers. In
some embodiments, the first and third most distal layers with
respect to the electrode are polycationic layers, and the second
most distal layer with respect to the electrode is a polyanionic
layer.
[0044] In an embodiment of the fifth aspect, the second domain
comprises at least five alternating polyelectrolyte layers. In some
embodiments, the first, third, and fifth most distal layers with
respect to the electrode are polycationic layers, and the second
and fourth most distal layers with respect to the electrode are
polyanionic layers.
[0045] In an embodiment of the fifth aspect, the second domain
comprises at least seven alternating polyelectrolyte layers. In
some embodiments, the first, third, fifth, and seventh most distal
layers with respect to the electrode are polycationic layers, and
the second, fourth, and sixth most distal layers with respect to
the sensor are polyanionic layers.
[0046] In an embodiment of the fifth aspect, the first domain is
distal to the second domain with respect to the electrode.
[0047] In an embodiment of the fifth aspect, the electrode
comprises an electroactive surface. In some embodiments, the second
domain contacts the electroactive surface.
[0048] In an embodiment of the fifth aspect, the polycationic layer
comprises a polycation with an average linear charge density from
about 2 to 10 e/.ANG., and the polyanionic layer comprises a
polyanion with an average linear charge density from about 2 to 10
e/.ANG..
[0049] In an embodiment of the fifth aspect, the polycationic layer
comprises a polycation with an average linear charge density from
about 2 to 3 e/.ANG., and the polyanionic layer comprises a
polyanion with an average linear charge density from about 2 to 3
e/.ANG..
[0050] In a sixth aspect, an implantable device is provided for
continuous measurement of glucose concentration, the device
comprising: an electrode configured to generate a signal indicative
of a concentration of an glucose in a host; and a membrane located
over the electrode, the membrane comprising: a first domain that
comprises an enzyme configured to react with glucose; a second
domain configured to reduce passage therethrough of an interferent,
the second domain comprising a plurality of alternating
polyelectrolyte layers, wherein the plurality of alternating
polyelectrolyte layers comprise a first polycationic layer, a first
polyanionic layer, and a second polycationic layer, wherein the
first polycationic layer and the second polycationic layer have at
least one characteristic that is different.
[0051] In an embodiment of the sixth aspect, the first polycationic
layer is formed of a first material, the second polycationic layer
is formed of a second material, and the first material is different
from the second material.
[0052] In an embodiment of the sixth aspect, the first polycationic
layer has a first average linear charge density, the second
polycationic layer has a second average linear charge density, and
the first average linear charge density is different than the
second average linear charge density.
[0053] In an embodiment of the sixth aspect, the electrode
comprises an electroactive surface. In some embodiments, the second
domain contacts the electroactive surface.
[0054] In a seventh aspect, an implantable device is provided for
continuous measurement of glucose concentration, the device
comprising: an electrode configured to generate a signal indicative
of a concentration of an glucose in a host; and a membrane located
over the electrode, the membrane comprising: a first domain that
comprises an enzyme configured to react with glucose; a second
domain configured to reduce passage therethrough of an interferent,
the second domain comprising a plurality of alternating
polyelectrolyte layers, wherein the plurality of alternating
polyelectrolyte layers comprise a first anionic layer, a first
polycationic layer, and a second polyanionic layer, wherein the
first polyanionic layer and the second polyanionic layer have at
least one characteristic that is different.
[0055] In an embodiment of the seventh aspect, the first
polyanionic layer is formed of a first material, the second
polyanionic layer is formed of a second material, and the first
material is different from the second material.
[0056] In an embodiment of the seventh aspect, the first
polyanionic layer has a first average linear charge density,
wherein the second polyanionic layer has a second average linear
charge density, and wherein the first average linear charge density
is different than the second average linear charge density.
[0057] In an embodiment of the seventh aspect, the electrode
comprises an electroactive surface. In some embodiments, the second
domain contacts the electroactive surface.
[0058] In an eighth aspect, an implantable device is provided for
continuous measurement of glucose concentration, the device
comprising: an electrode configured to generate a signal indicative
of a concentration of glucose in a host; and a membrane located
over the electrode, the membrane comprising: a first domain that
comprises an enzyme configured to react with glucose and produce
hydrogen peroxide; a second domain configured to reduce passage
therethrough of an interferent, the second domain comprising a
plurality of alternating polyelectrolyte layers, wherein the
plurality of alternating polyelectrolyte layers comprise at least
one of a polycationic layer and a polyanionic layer, whereby the
device is configured to exhibit a selectivity for acetaminophen
over hydrogen peroxide of less than about 0.5, wherein the
selectivity is determined by dividing a sensitivity of the device
for acetaminophen by a sensitivity of the device for hydrogen
peroxide, wherein the acetaminophen sensitivity is determined in
vitro by measuring the device's current response versus
concentrations of acetaminophen at 10 .mu.M aqueous acetaminophen,
50 .mu.M aqueous acetaminophen, and 100 .mu.M aqueous
acetaminophen, and then performing linear regression, and wherein
the hydrogen peroxide sensitivity is determined in vitro by
measuring the device's current response versus concentrations of
hydrogen peroxide at 1 .mu.M aqueous hydrogen peroxide, 2 .mu.M
aqueous hydrogen peroxide, and 3 .mu.M aqueous hydrogen peroxide,
and then performing linear regression.
[0059] In an embodiment of the eighth aspect, the electrode
comprises an electroactive surface. In some embodiments, the second
domain contacts the electroactive surface.
[0060] In an embodiment of the eighth aspect, the membrane further
comprises a third domain configured to reduce a flux therethrough
of glucose.
[0061] In an embodiment of the eighth aspect, the device is
configured to exhibit a selectivity for acetaminophen over hydrogen
peroxide of less than about 0.047.
[0062] In an embodiment of the eighth aspect, the device is
configured to exhibit a selectivity for acetaminophen over hydrogen
peroxide of less than about 0.013.
[0063] In an embodiment of the eighth aspect, the device is
configured to exhibit a selectivity for acetaminophen over hydrogen
peroxide of less than about 0.006.
[0064] In an embodiment of the eighth aspect, the polycationic
layer comprises a polycation with an average linear charge density
from about 2 to 10 e/.ANG., and wherein the polyanionic layer
comprises a polyanion with an average linear charge density from
about 2 to 10 e/.ANG..
[0065] In an embodiment of the eighth aspect, the polycationic
layer comprises a polycation with an average linear charge density
from about 2 to 3 e/.ANG., and wherein the polyanionic layer
comprises a polyanion with an average linear charge density from
about 2 to 3 e/.ANG..
BRIEF DESCRIPTION OF THE DRAWINGS
[0066] FIG. 1 is an expanded view of an exemplary embodiment of a
continuous analyte sensor.
[0067] FIGS. 2A-2C are cross-sectional views through the sensor of
FIG. 1 on line 2-2, illustrating various embodiments of the
membrane system.
[0068] FIG. 3 is a graph illustrating the components of a signal
measured by a glucose sensor (after sensor break-in was complete),
in a non-diabetic volunteer host.
[0069] FIG. 4A is a schematic view of a base polymer containing
surface-active end groups in one embodiment.
[0070] FIG. 4B is a schematic view of a bioprotective domain,
showing an interface in a biological environment (e.g.,
interstitial space or vascular space).
[0071] FIG. 5A is a graph illustrating the H.sub.2O.sub.2
selectivity of polyelectrolyte coated sensors having from one to
four layers versus a control.
[0072] FIG. 5B is a graph illustrating the interferent blocking
properties of polyelectrolyte coated sensors having from one to
four layers versus a control.
[0073] FIG. 6A is a graph illustrating the effect of PAA solution
pH on acetaminophen selectivity (PAH solution held at a pH of
10.0).
[0074] FIG. 6B is a graph illustrating the effect of PAH solution
pH on acetaminophen selectivity (PAA solution held at a pH of
3.0).
[0075] FIG. 7A is a graph illustrating the effect of PAA solution
pH on acetaminophen selectivity.
[0076] FIG. 7B is a graph illustrating the effect of PAH solution
pH on acetaminophen selectivity.
[0077] FIG. 8A is a graph comparing H.sub.2O.sub.2 and
acetaminophen sensitivity for various interference domains in
combination with an enzyme domain.
[0078] FIG. 8B is a graph illustrating the ratio of the sensitivity
of acetaminophen to the sensitivity of H.sub.2O.sub.2.
[0079] FIG. 9A is a schematic view of a portion of one embodiment
of an interference domain that comprises a plurality of
polycationic and polyanionic layers.
[0080] FIG. 9B illustrates one embodiment of a layer-by-layer
deposition method, which employs alternating adsorption of
polycations and polyanions to create a structure illustrated in
FIG. 9A
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0081] The following description and examples describe in detail
some exemplary embodiments of devices and methods for providing
continuous measurement of an analyte concentration. It should be
appreciated that there are numerous variations and modifications of
the devices and methods described herein that are encompassed by
the present invention. Accordingly, the description of a certain
exemplary embodiment should not be deemed to limit the scope of the
present invention.
Definitions
[0082] In order to facilitate an understanding of the devices and
methods described herein, a number of terms are defined below.
[0083] 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, urine,
sweat, saliva, etc.) that can be analyzed. Analytes can include
naturally occurring substances, artificial substances, metabolites,
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); biotimidase; biopterin;
c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin;
chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;
conjugated 1-.beta. hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
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, B); lysozyme; mefloquine;
netilmicin; phenobarbitone; phenyloin; 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 or endogenous, for
example, a metabolic product, a hormone, an antigen, an antibody,
and the like. Alternatively, the analyte can be introduced into the
body or exogenous, 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), and
5-hydroxyindoleacetic acid (FHIAA).
[0084] The phrase `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
(but regularly) performed, for example, about every 5 to 10
minutes.
[0085] The terms `operable connection,` `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 another component(s) in a manner that allows
transmission of signals between the components. For example, one or
more electrodes can be used to detect the amount of analyte in a
sample and convert that information into a signal; the signal can
then be transmitted to a circuit. In this case, the electrode is
`operably linked` to the electronic circuitry.
[0086] 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
(e.g., humans) and plants.
[0087] The terms `electrochemically reactive surface` and
`electroactive surface` 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 the surface
of an electrode where an electrochemical reaction takes place. As
one example, in a working electrode, H.sub.2O.sub.2 (hydrogen
peroxide) produced by an enzyme-catalyzed reaction of an analyte
being detected reacts and thereby creates a measurable electric
current. For example, in the detection of glucose, glucose oxidase
produces H.sub.2O.sub.2 as a byproduct. The H.sub.2O.sub.2 reacts
with the surface of the working electrode to produce two protons
(2H.sup.+), two electrons (2e.sup.-), and one molecule of oxygen
(O.sub.2), which produces the electric current being detected. In
the case of the counter electrode, a reducible species, for
example, O.sub.2 is reduced at the electrode surface in order to
balance the current being generated by the working electrode.
[0088] The terms `sensing region,` `sensor`, and `sensing
mechanism` 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 the region or mechanism
of a monitoring device responsible for the detection of a
particular analyte.
[0089] The terms `raw data stream` and `data stream` as used herein
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to an analog or digital signal directly related to the
measured glucose concentration from the glucose sensor. In one
example, the raw data stream is digital data in `counts` converted
by an A/D converter from an analog signal (for example, voltage or
amps) representative of a glucose concentration. The terms broadly
encompass a plurality of time spaced data points from a
substantially continuous glucose sensor, which comprises individual
measurements taken at time intervals ranging from fractions of a
second up to, for example, 1, 2, or 5 minutes or longer.
[0090] The term `counts` as used herein is a broad term, and is to
be given its ordinary and customary meaning to a person of ordinary
skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to a unit of
measurement of a digital signal. In one example, a raw data stream
measured in counts is directly related to a voltage (for example,
converted by an A/D converter), which is directly related to
current from the working electrode. In another example, counter
electrode voltage measured in counts is directly related to a
voltage.
[0091] The term `electrical potential` 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 electrical potential difference between two points in a circuit
which is the cause of the flow of a current.
[0092] The phrase `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. For example, some embodiments of a sensor
include a membrane system having a bioprotective domain and an
enzyme domain. If the sensor is deemed to be the point of reference
and the bioprotective domain is positioned farther from the sensor
than the enzyme domain, then the bioprotective domain is more
distal to the sensor than the enzyme domain.
[0093] The phrase `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. For example, some embodiments of a device
include a membrane system having a bioprotective domain and an
enzyme domain. If the sensor is deemed to be the point of reference
and the enzyme domain is positioned nearer to the sensor than the
bioprotective domain, then the enzyme domain is more proximal to
the sensor than the bioprotective domain.
[0094] 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 or species that interfere with the
measurement of an analyte of interest in a sensor to produce a
signal that does not accurately represent the analyte measurement.
In an exemplary electrochemical sensor, interfering species can
include compounds with an oxidation potential that overlaps with
that of the analyte to be measured.
[0095] 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 regions of a
membrane that can be layers, uniform or non-uniform gradients
(i.e., anisotropic) or provided as portions of the membrane.
[0096] The terms `sensing 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 refers
without limitation to a permeable or semi-permeable membrane that
can comprise one or more domains and constructed of materials of a
few microns thickness or more, which are permeable to oxygen and
may or may not be permeable to an analyte of interest. In one
example, the sensing membrane or membrane system may comprise an
immobilized glucose oxidase enzyme, which enables an
electrochemical reaction to occur to measure a concentration of
glucose.
[0097] The term `baseline` as used herein is a broad term, and is
to be given its ordinary and customary meaning to a person of
ordinary skill in the art (and is not to be limited to a special or
customized meaning), and refers without limitation to the 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 of the signal.
[0098] The term `sensitivity` 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 amount of
electrical current produced by a predetermined amount (unit) of the
measured analyte. For example, in one embodiment, a sensor has a
sensitivity (or slope) of from about 1 to about 100 picoAmps of
current for every 1 mg/dL of glucose analyte.
[0099] As employed herein, the following abbreviations apply: Eq
and Eqs (equivalents); mEq (milliequivalents); M (molar); mM
(millimolar); .mu.M (micromolar); N (Normal); mol (moles); mmol
(millimoles); .mu.mol (micromoles); nmol (nanomoles); g (grams); mg
(milligrams); .mu.g (micrograms); Kg (kilograms); L (liters); mL
(milliliters); dL (deciliters); .mu.L (microliters); cm
(centimeters); mm (millimeters); .mu.m (micrometers); nm
(nanometers); h and hr (hours); min. (minutes); s and sec.
(seconds); .degree. C. (degrees Centigrade).
Overview
[0100] Membrane systems of the various embodiments are suitable for
use with implantable devices in contact with a biological fluid.
For example, the membrane systems can be utilized with implantable
devices, such as devices for monitoring and determining analyte
levels in a biological fluid, for example, devices for monitoring
glucose levels for individuals having diabetes. In some
embodiments, the analyte-measuring device is a continuous device.
The analyte-measuring device can employ any suitable sensing
element to provide the raw signal, including but not limited to
those involving enzymatic, chemical, physical, electrochemical,
spectrophotometric, polarimetric, calorimetric, radiometric,
immunochemical, or like elements.
[0101] Although some of the description that follows is directed at
glucose-measuring devices, including the described membrane systems
and methods for their use, these membrane systems are not limited
to use in devices that measure or monitor glucose. These membrane
systems are suitable for use in any of a variety of devices,
including, for example, devices that detect and quantify other
analytes present in biological fluids (e.g., cholesterol, amino
acids, alcohol, galactose, and lactate), cell transplantation
devices (see, for example, U.S. Pat. No. 6,015,572, U.S. Pat. No.
5,964,745, and U.S. Pat. No. 6,083,523), drug delivery devices
(see, for example, U.S. Pat. No. 5,458,631, U.S. Pat. No.
5,820,589, and U.S. Pat. No. 5,972,369), and the like.
[0102] In one embodiment, the analyte sensor is an implantable
glucose sensor, such as described with reference to U.S. Pat. No.
6,001,067 and U.S. Patent Publication No. US-2005-0027463-A1. In
another embodiment, the analyte sensor is a glucose sensor, such as
described with reference to U.S. Patent Publication No.
US-2006-0020187-A1. In still other embodiments, the sensor is
configured to be implanted in a host vessel or extra-corporeally,
such as is described in U.S. Patent Publication No.
US-2007-0027385-A1, U.S. Patent Publication No. US-2008-0119703-A1,
U.S. Patent Publication No. US-2008-0108942-A1, and U.S. Patent
Publication No. US-2007-0197890-A1. In some embodiments, the sensor
is configured as a dual-electrode sensor, such as described in U.S.
Patent Publication No. US-2005-0143635-A1, U.S. Patent Publication
No. US-2007-0027385-A1, U.S. Patent Publication No.
US-2007-0213611-A1, and U.S. Patent Publication No.
US-2008-0083617-A1. In one alternative embodiment, the continuous
glucose sensor comprises a sensor such as described in U.S. Pat.
No. 6,565,509 to Say et al., for example. In another alternative
embodiment, the continuous glucose sensor comprises a subcutaneous
sensor such as described with reference to U.S. Pat. No. 6,579,690
to Bonnecaze et al. or U.S. Pat. No. 6,484,046 to Say et al., for
example. In another alternative embodiment, the continuous glucose
sensor comprises a refillable subcutaneous sensor such as described
with reference to U.S. Pat. No. 6,512,939 to Colvin et al., for
example. In yet another alternative embodiment, the continuous
glucose sensor comprises an intravascular sensor such as described
with reference to U.S. Pat. No. 6,477,395 to Schulman et al., for
example. In another alternative embodiment, the continuous glucose
sensor comprises an intravascular sensor such as described with
reference to U.S. Pat. No. 6,424,847 to Mastrototaro et al. In some
embodiments, the electrode system can be used with any of a variety
of known in vivo analyte sensors or monitors, such as U.S. Pat. No.
7,157,528 to Ward; U.S. Pat. No. 6,212,416 to Ward et al.; U.S.
Pat. No. 6,119,028 to Schulman et al.; U.S. Pat. No. 6,400,974 to
Lesho; U.S. Pat. No. 6,595,919 to Berner et al.; U.S. Pat. No.
6,141,573 to Kurnik et al.; U.S. Pat. No. 6,122,536 to Sun et al.;
European Patent Application EP 1153571 to Varall et al.; U.S. Pat.
No. 6,512,939 to Colvin et al.; U.S. Pat. No. 5,605,152 to Slate et
al.; U.S. Pat. No. 4,431,004 to Bessman et al.; U.S. Pat. No.
4,703,756 to Gough et al.; U.S. Pat. No. 6,514,718 to Heller et
al.; U.S. Pat. No. 5,985,129 to Gough et al.; WO Patent Application
Publication No. 04/021877 to Caduff; U.S. Pat. No. 5,494,562 to
Maley et al.; U.S. Pat. No. 6,120,676 to Heller et al.; and U.S.
Pat. No. 6,542,765 to Guy et al. In general, it is understood that
the disclosed embodiments are applicable to a variety of continuous
analyte measuring device configurations.
[0103] In some embodiments, a long term sensor (e.g., wholly
implantable or intravascular) is configured and arranged to
function for a time period of from about 30 days or less to about
one year or more (e.g., a sensor session). In some embodiments, a
short term sensor (e.g., one that is transcutaneous or
intravascular) is configured and arranged to function for a time
period of from about a few hours to about 30 days, including a time
period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,
16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 days
(e.g., a sensor session). As used herein, the term `sensor session`
is a broad term and refers without limitation to the period of time
the sensor is applied to (e.g., implanted in) the host or is being
used to obtain sensor values. For example, in some embodiments, a
sensor session extends from the time of sensor implantation (e.g.,
including insertion of the sensor into subcutaneous tissue and
placing the sensor into fluid communication with a host's
circulatory system) to the time when the sensor is removed.
Exemplary Glucose Sensor Configuration
[0104] FIG. 1 is an expanded view of an exemplary embodiment of a
continuous analyte sensor 34, also referred to as an analyte
sensor, illustrating the sensing mechanism. In some embodiments,
the sensing mechanism is adapted for insertion under the host's
skin, and the remaining body of the sensor (e.g., electronics,
etc.) can reside ex vivo. In the illustrated embodiment, the
analyte sensor 34 includes two electrodes, i.e., a working
electrode 38 and at least one additional electrode 30, which may
function as a counter or reference electrode, hereinafter referred
to as the reference electrode 30.
[0105] It is contemplated that the electrode may be formed to have
any of a variety of cross-sectional shapes. For example, in some
embodiments, the electrode may be formed to have a circular or
substantially circular shape, but in other embodiments, the
electrode may be formed to have a cross-sectional shape that
resembles an ellipse, a polygon (e.g., triangle, square, rectangle,
parallelogram, trapezoid, pentagon, hexagon, octagon), or the like.
In various embodiments, the cross-sectional shape of the electrode
may be symmetrical, but in other embodiments, the cross-sectional
shape may be asymmetrical. In some embodiments, each electrode may
be formed from a fine wire with a diameter of from about 0.001 or
less to about 0.050 inches or more, for example, and is formed
from, e.g., a plated insulator, a plated wire, or bulk electrically
conductive material. In some embodiments, the wire used to form a
working electrode may be about 0.002, 0.003, 0.004, 0.005, 0.006,
0.007, 0.008, 0.009, 0.01, 0.015, 0.02, 0.025, 0.03, 0.035, 0.04,
or 0.045 inches in diameter.
[0106] In some embodiments, the working electrode may comprise a
wire formed from a conductive material, such as platinum,
platinum-black, platinum-iridium, palladium, graphite, gold,
carbon, conductive polymer, alloys, or the like. Although the
illustrated electrode configuration and associated text describe
one method of forming a sensor, any of a variety of known sensor
configurations can be employed with the analyte sensor system.
[0107] The working electrode 38 is configured to measure the
concentration of an analyte, such as, but not limited to glucose,
uric acid, cholesterol, lactate, and the like. In an enzymatic
electrochemical sensor for detecting glucose, for example, the
working electrode may measure the hydrogen peroxide produced by an
enzyme catalyzed reaction of the analyte being detected and creates
a measurable electric current. For example, in the detection of
glucose wherein glucose oxidase (GOX) produces H.sub.2O.sub.2 as a
byproduct, the H.sub.2O.sub.2 reacts with the surface of the
working electrode producing two protons (2H.sup.+), two electrons
(2e.sup.-) and one molecule of oxygen (O.sub.2), which produces the
electric current being detected.
[0108] An insulator may be provided to electrically insulate the
working and reference electrodes. In this exemplary embodiment, the
working electrode 38 is covered with an insulating material, for
example, a non-conductive polymer. Dip-coating, spray-coating,
vapor-deposition, or other coating or deposition techniques can be
used to deposit the insulating material on the working electrode.
In one embodiment, the insulating material comprises parylene,
which can be an advantageous polymer coating because of its
strength, lubricity, and electrical insulation properties.
Generally, parylene is produced by vapor deposition and
polymerization of para-xylylene (or its substituted derivatives).
However, any suitable insulating material can be used, for example,
fluorinated polymers, polyethyleneterephthalate, polyurethane,
polyimide, other nonconducting polymers, or the like. Glass or
ceramic materials can also be employed. Other materials suitable
for use include surface energy modified coating systems such as
those 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.
[0109] In some embodiments, the reference electrode 30, which may
function as a reference electrode alone, or as a dual reference and
counter electrode, is formed from silver, silver/silver chloride,
or the like. In some embodiments, the electrodes are
juxtapositioned or twisted with or around each other, but it is
contemplated, however, that other configurations are also possible.
In one embodiment, the reference electrode 30 is helically wound
around the working electrode 38. The assembly of wires may then be
optionally coated together with an insulating material, similar to
that described above, in order to provide an insulating attachment
(e.g., securing together of the working and reference
electrodes).
[0110] 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, or 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.
[0111] In some embodiments, a radial window is formed through the
insulating material 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. In some applications, cellular attack
or migration of cells to the sensor can cause reduced sensitivity
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. Additional embodiments of electrode
configurations are described U.S. Patent Publication No.
US-2011-0027127-A1, which is incorporated herein by reference in
its entirety.
[0112] In some alternative embodiments, additional electrodes can
be included within the assembly, for example, a three-electrode
system (working, reference, and counter electrodes) and 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. Pat. No. 7,081,195, U.S. Patent Publication No.
US-2005-0143635-A1 and U.S. Patent Publication No.
US-2007-0027385-A1 describe some systems and methods for
implementing and using additional working, counter, and reference
electrodes. In one implementation wherein the sensor comprises two
working electrodes, the two working electrodes are juxtapositioned,
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 signals, and the additional working
electrode is configured to measure a baseline signal consisting of
the baseline signal only. In these embodiments, the second working
electrode may be configured to be substantially similar to the
first working electrode, but without an enzyme disposed thereon. In
this way, the baseline signal can be determined and subtracted from
the first signal to generate a difference signal, i.e., a
glucose-only signal that is substantially not subject to
fluctuations in the baseline or interfering species on the signal,
such as described in U.S. Patent Publication No.
US-2005-0143635-A1, U.S. Patent Publication No. US-2007-0027385-A1,
and U.S. Patent Publication No. US-2007-0213611-A1, and U.S. Patent
Publication No. US-2008-0083617-A1.
[0113] It has been found that in some electrode systems involving
two working electrodes, i.e., in some dual-electrode systems, the
working electrodes may sometimes be slightly different from each
other. For instance, two working electrodes, even when manufactured
from a single facility may slightly differ in thickness or
permeability because of the electrodes' high sensitivity to
environmental conditions (e.g., temperature, humidity) during
fabrication. Accordingly, the working electrodes of a
dual-electrode system may sometimes have varying diffusion,
membrane thickness, and diffusion characteristics. As a result, the
above-described difference signal (i.e., a glucose-only signal,
generated from subtracting the baseline signal from the first
signal) may not be completely accurate. To mitigate this, it is
contemplated that in some dual-electrode systems, both working
electrodes may be fabricated with one or more membranes that each
includes a bioprotective layer, which is described in more detail
elsewhere herein.
[0114] It is contemplated that the sensing region may include any
of a variety of electrode configurations. For example, in some
embodiments, in addition to one or more glucose-measuring working
electrodes, the sensing region may also include a reference
electrode or other electrodes associated with the working
electrode. In these particular embodiments, the sensing region may
also include a separate reference or counter electrode associated
with one or more optional auxiliary working electrodes. In other
embodiments, the sensing region may include a glucose-measuring
working electrode, an auxiliary working electrode, two counter
electrodes (one for each working electrode), and one shared
reference electrode. In yet other embodiments, the sensing region
may include a glucose-measuring working electrode, an auxiliary
working electrode, two reference electrodes, and one shared counter
electrode.
[0115] U.S. Patent Publication No. US-2008-0119703-A1 and U.S.
Patent Publication No. US-2005-0245799-A1 describes additional
configurations for using the continuous sensor in different body
locations. In some embodiments, the sensor is configured for
transcutaneous implantation in the host. In alternative
embodiments, the sensor is configured for insertion into the
circulatory system, such as a peripheral vein or artery. However,
in other embodiments, the sensor is configured for insertion into
the central circulatory system, such as but not limited to the vena
cava. In still other embodiments, the sensor can be placed in an
extracorporeal circulation system, such as but not limited to an
intravascular access device providing extracorporeal access to a
blood vessel, an intravenous fluid infusion system, an
extracorporeal blood chemistry analysis device, a dialysis machine,
a heart-lung machine (i.e., a device used to provide blood
circulation and oxygenation while the heart is stopped during heart
surgery), etc. In still other embodiments, the sensor can be
configured to be wholly implantable, as described in U.S. Pat. No.
6,001,067.
[0116] FIG. 2A is a cross-sectional view through the sensor of FIG.
1 on line 2-2, illustrating one embodiment of the membrane system
32. In this particular embodiment, the membrane system includes an
enzyme domain 42, a diffusion resistance domain 44, and a
bioprotective domain 46 located around the working electrode 38,
all of which are described in more detail elsewhere herein. In some
embodiments, a unitary diffusion resistance domain and
bioprotective domain may be included in the membrane system (e.g.,
wherein the functionality of both domains is incorporated into one
domain, i.e., the bioprotective domain). In some embodiments, the
sensor is configured for short-term implantation (e.g., from about
1 to 30 days). However, it is understood that the membrane system
32 can be modified for use in other devices, for example, by
including only one or more of the domains, or additional
domains.
[0117] In some embodiments, the membrane system may include a
bioprotective domain 46, also referred to as a cell-impermeable
domain or biointerface domain, comprising a surface-modified base
polymer as described in more detail elsewhere herein. However, the
sensing membranes 32 of some embodiments can also include a
plurality of domains or layers including, for example, an electrode
domain (e.g., as illustrated in the FIG. 2C), an interference
domain (e.g., as illustrated in FIG. 2B), or a cell disruptive
domain (not shown), such as described in more detail elsewhere
herein and in U.S. Patent Publication No. US-2006-0036145-A1.
[0118] It is to be understood that sensing membranes modified for
other sensors, for example, may include fewer or additional layers.
For example, in some embodiments, the membrane system may comprise
one electrode layer, one enzyme layer, and two bioprotective
layers, but in other embodiments, the membrane system may comprise
one electrode layer, two enzyme layers, and one bioprotective
layer. In some embodiments, the bioprotective layer may be
configured to function as the diffusion resistance domain and
control the flux of the analyte (e.g., glucose) to the underlying
membrane layers.
[0119] In some embodiments, one or more domains of the sensing
membranes may be formed from materials such as silicone,
polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene,
polyolefin, polyester, polycarbonate, biostable
polytetrafluoroethylene, homopolymers, copolymers, terpolymers of
polyurethanes, polypropylene (PP), polyvinylchloride (PVC),
polyvinylidene fluoride (PVDF), polybutylene terephthalate (PBT),
polymethylmethacrylate (PMMA), polyether ether ketone (PEEK),
polyurethanes, cellulosic polymers, poly(ethylene oxide),
poly(propylene oxide) and copolymers and blends thereof,
polysulfones and block copolymers thereof including, for example,
di-block, tri-block, alternating, random and graft copolymers.
[0120] In some embodiments, the sensing membrane can be deposited
on the electroactive surfaces of the electrode material using known
thin or thick film techniques (for example, spraying,
electro-depositing, dipping, or the like). It should be appreciated
that the sensing membrane located over the working electrode does
not have to have the same structure as the sensing membrane located
over the reference electrode; for example, the enzyme domain
deposited over the working electrode does not necessarily need to
be deposited over the reference or counter electrodes.
[0121] Although the exemplary embodiments illustrated in FIGS.
2A-2C involve circumferentially extending membrane systems, the
membranes described herein may be applied to any planar or
non-planar surface, for example, the substrate-based sensor
structure of U.S. Pat. No. 6,565,509 to Say et al.
Sensor Electronics
[0122] In general, analyte sensor systems have electronics
associated therewith, also referred to as a `computer system` that
can include hardware, firmware, or software that enable measurement
and processing of data associated with analyte levels in the host.
In one exemplary embodiment of an electrochemical sensor, the
electronics include a potentiostat, a power source for providing
power to the sensor, and other components useful for signal
processing. In additional embodiments, some or all of the
electronics can be in wired or wireless communication with the
sensor 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 (e.g., a receiver), such as by infrared
(IR) or RF. It is contemplated that other embodiments of
electronics may be useful for providing sensor data output, such as
those described in U.S. Patent Publication No. US-2005-0192557-A1,
U.S. Patent Publication No. US-2005-0245795-A1; U.S. Patent
Publication No. US-2005-0245795-A1, and U.S. Patent Publication No.
US-2005-0245795-A1, U.S. Patent Publication No. US-2008-0119703-A1,
and U.S. Patent Publication No. US-2008-0108942-A1.
[0123] In one embodiment, a potentiostat is operably connected to
the electrode(s) (such as described elsewhere herein), 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. 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.
[0124] In general, 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 or replacement of signal artifacts such as is
described in U.S. Patent Publication No. US-2005-0043598-A1). The
processor additionally can be used for the system's cache memory,
for example for temporarily storing recent sensor data. In some
embodiments, the processor module comprises memory storage
components such as ROM, RAM, dynamic-RAM, static-RAM, non-static
RAM, EEPROM, rewritable ROMs, flash memory, and the like.
[0125] 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. 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.
[0126] 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, or an integrated value) or error detection or correction. The
data (transmission) packet can have a length of from about 8 bits
to about 128 bits, or, for example, of 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 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).
[0127] 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.
[0128] In some embodiments, an output module, which is integral
with 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.
Noise
[0129] Generally, implantable sensors measure a signal related to
an analyte of interest in a host. For example, an electrochemical
sensor can measure glucose, creatinine, or urea in a host, such as
an animal (e.g., a human). Generally, the signal is converted
mathematically to a numeric value indicative of analyte status,
such as analyte concentration, as described in more detail
elsewhere herein. In general, the signal generated by conventional
analyte sensors contains some noise. Noise is clinically important
because it can induce error and can reduce sensor performance, such
as by providing a signal that causes the analyte concentration to
appear higher or lower than the actual analyte concentration. For
example, upward or high noise (e.g., noise that causes the signal
to increase) can cause the reading of the host's glucose
concentration to appear higher than the actual value, which in turn
can lead to improper treatment decisions. Similarly, downward or
low noise (e.g., noise that causes the signal to decrease) can
cause the reading of the host's glucose concentration to appear
lower than its actual value, which in turn can also lead to
improper treatment decisions. Accordingly, noise reduction is
desirable.
[0130] In general, the signal detected by the sensor can be broken
down into its component parts. For example, in one embodiment of an
enzymatic electrochemical analyte sensor, after sensor break-in is
complete, the total signal can be divided into an `analyte
component,` which is representative of analyte (e.g., glucose)
concentration, and a `noise component,` which is caused by
non-analyte-related species that have a redox potential that
substantially overlaps with the redox potential of the analyte (or
measured species, e.g., H.sub.2O.sub.2) at an applied voltage. The
noise component can be further divided into its component parts,
e.g., constant and non-constant noise. It is not unusual for a
sensor to experience a certain level of noise. In general,
`constant noise` (sometimes referred to as constant background or
baseline) is caused by non-analyte-related factors that are
relatively stable over time, including but not limited to
electroactive species that arise from generally constant (e.g.,
daily) metabolic processes. Constant noise can vary widely between
hosts. In contrast, `non-constant noise` (sometimes referred to as
non-constant background) is generally caused by non-constant,
non-analyte-related species (e.g., non-constant noise-causing
electroactive species) that may arise during transient events, such
as during host metabolic processes (e.g., wound healing or in
response to an illness), or due to ingestion of certain compounds
(e.g., certain drugs). In some circumstances, noise can be caused
by a variety of noise-causing electroactive species, which are
discussed in detail elsewhere herein.
[0131] FIG. 3 is a graph illustrating the components of a signal
measured by a transcutaneous glucose sensor (after sensor break-in
was complete), in a non-diabetic volunteer host. The Y-axis
indicates the signal amplitude (in counts) detected by the sensor.
The total signal collected by the sensor is represented by line
1000, which includes components related to glucose, constant noise,
and non-constant noise, which are described in more detail
elsewhere herein. In some embodiments, the total signal is a raw
data stream, which can include an averaged or integrated signal,
for example, using a charge-counting device.
[0132] The non-constant noise component of the total signal is
represented by line 1010. The non-constant noise component 1010 of
the total signal 1000 can be obtained by filtering the total signal
1000 to obtain a filtered signal 1020 using any of a variety of
known filtering techniques, and then subtracting the filtered
signal 1020 from the total signal 1000. In some embodiments, the
total signal can be filtered using linear regression analysis of
the n (e.g., 10) most recent sampled sensor values. In some
embodiments, the total signal can be filtered using non-linear
regression. In some embodiments, the total signal can be filtered
using a trimmed regression, which is a linear regression of a
trimmed mean (e.g., after rejecting wide excursions of any point
from the regression line). In this embodiment, after the sensor
records glucose measurements at a predetermined sampling rate
(e.g., every 30 seconds), the sensor calculates a trimmed mean
(e.g., removes highest and lowest measurements from a data set) and
then regresses the remaining measurements to estimate the glucose
value. In some embodiments, the total signal can be filtered using
a non-recursive filter, such as a finite impulse response (FIR)
filter. An FIR filter is a digital signal filter, in which every
sample of output is the weighted sum of past and current samples of
input, using only some finite number of past samples. In some
embodiments, the total signal can be filtered using a recursive
filter, such as an infinite impulse response (IIR) filter. An IIR
filter is a type of digital signal filter, in which every sample of
output is the weighted sum of past and current samples of input. In
some embodiments, the total signal can be filtered using a
maximum-average (max-average) filtering algorithm, which smoothes
data based on the discovery that the substantial majority of signal
artifacts observed after implantation of glucose sensors in humans,
for example, is not distributed evenly above and below the actual
blood glucose levels. It has been observed that many data sets are
actually characterized by extended periods in which the noise
appears to trend downwardly from maximum values with occasional
high spikes. To overcome these downward trending signal artifacts,
the max-average calculation tracks with the highest sensor values,
and discards the bulk of the lower values. Additionally, the
max-average method is designed to reduce the contamination of the
data with unphysiologically high data from the high spikes. The
max-average calculation smoothes data at a sampling interval (e.g.,
every 30 seconds) for transmission to the receiver at a less
frequent transmission interval (e.g., every 5 minutes), to minimize
the effects of low non-physiological data. First, the
microprocessor finds and stores a maximum sensor counts value in a
first set of sampled data points (e.g., 5 consecutive, accepted,
thirty-second data points). A frame shift time window finds a
maximum sensor counts value for each set of sampled data (e.g.,
each 5-point cycle length) and stores each maximum value. The
microprocessor then computes a rolling average (e.g., 5-point
average) of these maxima for each sampling interval (e.g., every 30
seconds) and stores these data. Periodically (e.g., every 10.sup.th
interval), the sensor outputs to the receiver the current maximum
of the rolling average (e.g., over the last 10 thirty-second
intervals as a smoothed value for that time period (e.g., 5
minutes)). In some embodiments, the total signal can be filtered
using a `Cone of Possibility Replacement Method,` which utilizes
physiological information along with glucose signal values in order
define a `cone` of physiologically feasible glucose signal values
within a human. Particularly, physiological information depends
upon the physiological parameters obtained from continuous studies
in the literature as well as our own observations. A first
physiological parameter uses a maximal sustained rate of change of
glucose in humans (e.g., about 4 to 6 mg/di/min) and a maximum
sustained acceleration of that rate of change (e.g., about 0.1 to
0.2 mg/min/min). A second physiological parameter uses the
knowledge that rate of change of glucose is lowest at the maxima
and minima, which are the areas of greatest risk in patient
treatment. A third physiological parameter uses the fact that the
best solution for the shape of the curve at any point along the
curve over a certain time period (e.g., about 20-25 minutes) is a
straight line. It is noted that the maximum rate of change can be
narrowed in some instances. Therefore, additional physiological
data can be used to modify the limits imposed upon the Cone of
Possibility Replacement Method for sensor glucose values. For
example, the maximum per minute rate of change can be lower when
the subject is lying down or sleeping; on the other hand, the
maximum per minute rate change can be higher when the subject is
exercising, for example. In some embodiments, the total signal can
be filtered using reference changes in electrode potential to
estimate glucose sensor data during positive detection of signal
artifacts from an electrochemical glucose sensor, the method
hereinafter referred to as reference drift replacement; in this
embodiment, the electrochemical glucose sensor comprises working,
counter, and reference electrodes. This method exploits the
function of the reference electrode as it drifts to compensate for
counter electrode limitations during oxygen deficits, pH changes,
or temperature changes. In alternative implementations of the
reference drift method, a variety of algorithms can therefore be
implemented based on the changes measured in the reference
electrode. Linear algorithms, and the like, are suitable for
interpreting the direct relationship between reference electrode
drift and the non-glucose rate limiting signal noise such that
appropriate conversion to signal noise compensation can be derived.
Additional description of signal filtering can be found in U.S.
Patent Publication No. US-2005-0043598-A1.
[0133] The constant noise signal component 1030 can be obtained by
calibrating the sensor signal using reference data, such as one or
more blood glucose values obtained from a hand-held blood glucose
meter, or the like, from which the baseline `b` of a regression can
be obtained, representing the constant noise signal component
1030.
[0134] The analyte signal component 1040 can be obtained by
subtracting the constant noise signal component 1030 from the
filtered signal 1020.
[0135] In general, non-constant noise is caused by interfering
species (non-constant noise-causing species), which can be
compounds, such as drugs that have been administered to the host,
or intermittently produced products of various host metabolic
processes. Exemplary interferents include but are not limited to a
variety of drugs (e.g., acetaminophen), H.sub.2O.sub.2 from
exterior sources (e.g., produced outside the sensor membrane
system), and reactive metabolic species (e.g., reactive oxygen and
nitrogen species, some hormones, etc.). Some known interfering
species for a glucose sensor include but are not limited to
acetaminophen, ascorbic acid, bilirubin, cholesterol, creatinine,
dopamine, ephedrine, ibuprofen, L-dopa, methyldopa, salicylate,
tetracycline, tolazamide, tolbutamide, triglycerides, and uric
acid.
[0136] In some experiments of implantable glucose sensors, it was
observed that noise increased when some hosts were intermittently
sedentary, such as during sleep or sitting for extended periods.
When the host began moving again, the noise quickly dissipated.
Noise that occurs during intermittent, sedentary periods (sometimes
referred to as intermittent sedentary noise) can occur during
relatively inactive periods, such as sleeping. Non-constant,
non-analyte-related factors can cause intermittent sedentary noise,
such as was observed in one exemplary study of non-diabetic
individuals implanted with enzymatic-type glucose sensors built
without enzyme. These sensors (without enzyme) could not react with
or measure glucose and therefore provided a signal due to
non-glucose effects only (e.g., constant and non-constant noise).
During sedentary periods (e.g., during sleep), extensive, sustained
signal was observed on the sensors. Then, when the host got up and
moved around, the signal rapidly corrected. As a control, in vitro
experiments were conducted to determine if a sensor component might
have leached into the area surrounding the sensor and caused the
noise, but none was detected. From these results, it is believed
that a host-produced non-analyte related reactant was diffusing to
the electrodes and producing the unexpected non-constant noise
signal.
Interferents
[0137] Interferents are molecules or other species that may cause a
sensor to generate a false positive or negative analyte signal
(e.g., a non-analyte-related signal). Some interferents are known
to become reduced or oxidized at the electrochemically reactive
surfaces of the sensor, while other interferents are known to
interfere with the ability of the enzyme (e.g., glucose oxidase)
used to react with the analyte being measured. Yet other
interferents are known to react with the enzyme (e.g., glucose
oxidase) to produce a byproduct that is electrochemically active.
Interferents can exaggerate or mask the response signal, thereby
leading to false or misleading results. For example, a false
positive signal may cause the host's analyte concentration (e.g.,
glucose concentration) to appear higher than the true analyte
concentration. False-positive signals may pose a clinically
significant problem in some conventional sensors. For example in a
severe hypoglycemic situation, in which the host has ingested an
interferent (e.g., acetaminophen), the resulting artificially high
glucose signal can lead the host to believe that he is euglycemic
or hyperglycemic. In response, the host may make inappropriate
treatment decisions, such as by injecting himself with too much
insulin, or by taking no action, when the proper course of action
would be to begin eating. In turn, this inappropriate action or
inaction may lead to a dangerous hypoglycemic episode for the host.
Accordingly, it is desired that a membrane system can be developed
that substantially reduces or eliminates the effects of
interferents on analyte measurements. As described in more detail
elsewhere herein, it is contemplated that a membrane system having
one or more domains capable of blocking or substantially reducing
the flow of interferents onto the electroactive surfaces of the
electrode may reduce noise and improve sensor accuracy.
[0138] With respect to analyte sensors, it is contemplated that a
number of types of interferents may cause inaccurate readings. One
type of interferents is defined herein as `exogenous interferents.`
The term `exogenous interferents` 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
interferents that affect the measurement of glucose and that are
present in the host, but that have origins outside of the body, and
that can include items administered to a person, such as
medicaments, drugs, foods or herbs, whether administered
intravenously, orally, topically, etc. By way of example,
acetaminophen ingested by a host or the lidocaine injected into a
host would be considered herein as exogenous interferents.
[0139] Another type of interferents is defined herein as
`endogenous interferents.` The term `endogenous interferents` 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 interferents that affect the measurement of
glucose and that have origins within the body, and thus includes
interferents derived from species or metabolites produced during
cell metabolism (e.g., as a result of wound healing). While not
wishing to be bound by theory, it is believed that a local buildup
of electroactive interferents, such as electroactive metabolites
derived from cellular metabolism and wound healing, may interfere
with sensor function and cause early intermittent, sedentary noise.
Local lymph pooling, when parts of the body are compressed or when
the body is inactive, may also cause, in part, this local buildup
of interferents (e.g., electroactive metabolites). It should be
noted that endogenous interferents may react with the membrane
system in ways that are different from exogenous interferents.
Endogenous interferents may include but are not limited to
compounds with electroactive acidic, amine or sulfhydryl groups,
urea (e.g., as a result of renal failure), lactic acid, phosphates,
citrates, peroxides, amino acids (e.g., L-arginine), amino acid
precursors or break-down products, nitric oxide (NO), NO-donors,
NO-precursors, or other electroactive species or metabolites
produced during cell metabolism or wound healing, for example.
Noise-Reducing Membrane System
[0140] In some embodiments, the continuous sensor may have a
bioprotective domain which includes a polymer containing one or
more surface-active groups configured to substantially reduce or
block the effect or influence of non-constant noise-causing
species. In some of these embodiments, the reduction or blocking of
the effect or influence of non-constant noise-causing species may
be such that the non-constant noise component of the signal is less
than about 60%, 50%, 40%, 30%, 20%, or 10% of the total signal. In
some embodiments, the sensor may include at least one electrode and
electronics configured to provide a signal measured at the
electrode. The measured signal can be broken down (e.g., after
sensor break-in) into its component parts, which may include but
are not limited to a substantially analyte-related component, a
substantially constant non-analyte-related component (e.g.,
constant noise), and a substantially non-constant
non-analyte-related component (e.g., non-constant noise). In some
of these embodiments, the sensor may be configured such that the
substantially non-constant non-analyte-related component does not
substantially contribute to the signal for at least about one or
two days. In some embodiments, the signal contribution of the
non-constant noise may be less than about 60%, 50%, 40%, 30%, 20%,
or 10% of the signal (i.e., total signal) over a time period of at
least about one day, but in other embodiments, the time period may
be at least about two, three, four, five, six, seven days or more,
including weeks or months, and the signal contribution of the
non-constant noise may be less than about 18%, 16%, 14%, 12%, 10%,
8%, 6%, 5%, 4%, 3%, 2%, or 1%. It is contemplated that in some
embodiments, the sensor may be configured such that the signal
contribution of the analyte-related component is at least about
50%, 60%, 70%, 80%, 90% or more of the total signal over a time
period of at least about one day; but in some embodiments, the time
period may be at least about two, three, four, five, six, seven
days or more, including weeks or months, and the signal
contribution of the analyte-related component may be at least about
50%, 55%, 60%, 65%, 70%, 75%, 80%, 82%, 84%, 86%, 88%, 90%, 91%,
92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more.
[0141] A signal component's percentage of the total signal can be
determined using a variety of methods of quantifying an amplitude
of signal components and total signal, from which each component's
percent contribution can be calculated. In some embodiments, the
signal components can be quantified by comparing the peak-to-peak
amplitudes of each signal component for a time period, whereby the
peak-to-peak amplitudes of each component can be compared to the
peak-to-peak amplitude of the total signal to determine its
percentage of the total signal. In some embodiments, the signal
components can be quantified by determining the Root Mean Square
(RMS) of the signal component for a time period. In one exemplary
of Root Mean Square analysis of signal components, the signal
component(s) can be quantified using the formula:
RMS = ( x 1 2 + x 2 2 + x 3 2 + x n 2 ) n ##EQU00001##
wherein there are a number (n) of data values (x) for a signal
(e.g., analyte component, non-constant noise component, constant
noise component, and total signal) during a predetermined time
period (e.g., about 1 day, about 2 days, about 3 days, etc.). Once
the signal components and total signal are quantified, the signal
components can be compared to the total signal to determine a
percentage of each signal component within the total signal.
Bioprotective Domain
[0142] The bioprotective domain is the domain or layer of an
implantable device configured to interface with (e.g., contact) a
biological fluid when implanted in a host or connected to the host
(e.g., via an intravascular access device providing extracorporeal
access to a blood vessel). As described above, membranes of some
embodiments may include a bioprotective domain 46 (see FIGS.
2A-2C), also referred to as a bioprotective layer, including at
least one polymer containing a surface-active group. In some
embodiments, the surface-active group-containing polymer is a
surface-active end group-containing polymer. In some of these
embodiments, the surface-active end group-containing polymer is a
polymer having covalently bonded surface-active end groups.
However, it is contemplated that other surface-active
group-containing polymers may also be used and can be formed by
modification of fully-reacted base polymers via the grafting of
side chain structures, surface treatments or coatings applied after
membrane fabrication (e.g., via surface-modifying additives),
blending of a surface-modifying additive to a base polymer before
membrane fabrication, immobilization of the
surface-active-group-containing soft segments by physical
entrainment during synthesis, or the like.
[0143] Base polymers useful for certain embodiments may include any
linear or branched polymer on the backbone structure of the
polymer. Suitable base polymers may include, but are not limited
to, epoxies, polyolefins, polysiloxanes, polyethers, acrylics,
polyesters, carbonates, and polyurethanes, wherein polyurethanes
may include polyurethane copolymers such as
polyether-urethane-urea, polycarbonate-urethane,
polyether-urethane, silicone-polyether-urethane,
silicone-polycarbonate-urethane, polyester-urethane, and the like.
In some embodiments, base polymers may be selected for their bulk
properties, such as, but not limited to, tensile strength, flex
life, modulus, and the like. For example, polyurethanes are known
to be relatively strong and to provide numerous reactive pathways,
which properties may be advantageous as bulk properties for a
membrane domain of the continuous sensor.
[0144] In some embodiments, a base polymer synthesized to have
hydrophilic segments may be used to form the bioprotective layer.
For example, a linear base polymer including biocompatible
segmented block polyurethane copolymers comprising hard and soft
segments may be used. In some embodiments, the hard segment of the
copolymer may have a molecular weight of from about 160 daltons to
about 10,000 daltons, and sometimes from about 200 daltons to about
2,000 daltons. In some embodiments, the molecular weight of the
soft segment may be from about 200 daltons to about 10,000,000
daltons, and sometimes from about 500 daltons to about 5,000,000
daltons, and sometimes from about 500,00 daltons to about 2,000,000
daltons. It is contemplated that polyisocyanates used for the
preparation of the hard segments of the copolymer may be aromatic
or aliphatic diisocyanates. The soft segments used in the
preparation of the polyurethane may be a polyfunctional aliphatic
polyol, a polyfunctional aliphatic or aromatic amine, or the like
that may be useful for creating permeability of the analyte (e.g.,
glucose) therethrough, and may include, for example, polyvinyl
acetate (PVA), poly(ethylene glycol) (PEG), polyacrylamide,
acetates, polyethylene oxide (PEO), polyethylacrylate (PEA),
polyvinylpyrrolidone (PVP), and variations thereof (e.g., PVP vinyl
acetate), and wherein PVP and variations thereof may be selected
for their hydrolytic stability in some embodiments.
[0145] Alternatively, in some embodiments, the bioprotective layer
may comprise a combination of a base polymer (e.g., polyurethane)
and one or more hydrophilic polymers, such as, PVA, PEG,
polyacrylamide, acetates, PEO, PEA, PVP, and variations thereof
(e.g., PVP vinyl acetate), e.g., as a physical blend or admixture
wherein each polymer maintains its unique chemical nature. It is
contemplated that any of a variety of combination of polymers may
be used to yield a blend with desired glucose, oxygen, and
interference permeability properties. For example, in some
embodiments, the bioprotective layer may be formed from a blend of
a polycarbonate-urethane base polymer and PVP, but in other
embodiments, a blend of a polyurethane, or another base polymer,
and one or more hydrophilic polymers may be used instead. In some
of the embodiments involving use of PVP, the PVP portion of the
polymer blend may comprise from about 5% to about 50% by weight of
the polymer blend, sometimes from about 15% to 20%, and other times
from about 25% to 40%. It is contemplated that PVP of various
molecular weights may be used. For example, in some embodiments,
the molecular weight of the PVP used may be from about 25,000
daltons to about 5,000,000 daltons, sometimes from about 50,000
daltons to about 2,000,000 daltons, and other times from 6,000,000
daltons to about 10,000,000 daltons.
[0146] Membranes have been developed that are capable of
controlling the flux of a particular analyte passing through the
membrane. However, it is known that conventional membranes
typically lack the capability of substantially reducing or blocking
the flux of interferents passing therethrough. From a membrane
design perspective, typically as a membrane is made more permeable
(i.e., opened up) for an analyte to pass through, this increased
permeability of the membrane for the analyte tends to also increase
the permeability of interferents. As an example, a conventional
membrane that allows for a flux of glucose (with a M.W. of 180
daltons) through the membrane will typically not substantially
reduce or block the flux of interferents, such as acetaminophen
(with a M.W. of 151.2 daltons) through the membrane. Accordingly,
without a mechanism designed to reduce the flux of interferents,
large levels of undesirable signal noise may be generated as a
result of the interferents passing through the membrane.
Advantageously, some embodiments described herein provide a
membrane layer that overcomes the above-described deficiencies by
providing a mechanism for selectively controlling the flux of a
particular analyte, while also substantially reducing or blocking
the flux of interferents through the membrane.
[0147] While not wishing to be bound by theory, it is believed that
in some conventional membranes formed with various segmented block
polyurethane copolymers, the hydrophobic portions of the copolymer
(e.g., the hard segments) may tend to segregate from the
hydrophilic portions (e.g., the soft segments), which in turn, may
cause the hydrophilic portions to align and form channels, through
which analytes, such as glucose, and other molecules, such as
exogenous interferents like acetaminophen, may pass through the
bioprotective layer from the distal surface to the proximal
surface. While the diffusion of analytes through the bioprotective
layer is desired, the diffusion of interferents is generally not.
Through experiments, it has been unexpectedly found that the use of
PVP blended with a base polymer, such as,
silicone-polycarbonate-urethane, may provide the bioprotective
layer with the capability of substantially reducing or blocking the
flux of various interferents, such as acetaminophen, through the
layer. While not wishing to be bound by theory, it is believed that
the carbonyl groups of PVP molecules may form hydrogen bonds with
various interferents. For example, acetaminophen molecules are
known to be capable of hydrogen bonding via their hydroxyl (O--H)
and amide (H--N--(C.dbd.O)) groups, and thus through these moieties
may interact with PVP. Although PVP is described here to provide an
example of a hydrophilic polymer capable of providing the hydrogen
bonding effects described above, it is contemplated that any of a
variety of other hydrophilic polymers known to have strong hydrogen
bonding properties may also be used, such as, polyvinyl
pyrrolidone-vinyl acetate (PVP-VA), hydroxypropyl cellulose (HPC),
hydroxypropyl methylcellulose (HPMC), for example.
[0148] In some embodiments, the bioprotective domain is configured
to substantially reduce or block the flux of at least one
interferent, and exhibits a glucose-to-interferent permeability
ratio of approximately 1 to 30, but in other embodiments the
glucose-to-interferent permeability ratio (e.g.,
glucose-to-acetaminophen permeability ratio) may be less than
approximately 1 to 1, 1 to 2, 1 to 5, 1 to 10, 1 to 15, 1 to 20, 1
to 35, 1 to 40, 1 to 45, 1 to 50, or 1 to 100. The
glucose-to-interferent permeability ratios exhibited by these
embodiments are an improvement over conventional polyurethane
membranes which typically exhibit glucose-to-interferent
permeability ratios (e.g., glucose-to-acetaminophen permeability
ratios) greater than 1 to 300. In some embodiments, the equivalent
peak glucose response to a 1,000 mg dose of acetaminophen is less
than about 100 mg/dL, sometimes less than 80 mg/dL, and sometimes
between about 50 mg/dL, and sometimes less than 20 mg/dL.
[0149] In some embodiments, the PVP portion of the polymer blend
may comprise from about 5% to about 50% by weight of the polymer
blend, sometimes from about 15% to 20%, and other times from about
25% to 40%. It is contemplated that PVP of various molecular
weights may be used. For example, in some embodiments, the
molecular weight of the PVP used may be from about 25,000 daltons
to about 5,000,000 daltons, sometimes from about 50,000 daltons to
about 2,000,000 daltons, and other times from 6,000,000 daltons to
about 10,000,000 daltons.
[0150] The term `surface-active group` and `surface-active end
group` as used herein are broad terms and are used in their
ordinary sense, including, without limitation, surface-active
oligomers or other surface-active moieties having surface-active
properties, such as alkyl groups, which preferentially migrate
towards a surface of a membrane formed there from. Surface-active
groups preferentially migrate toward air (e.g., driven by
thermodynamic properties during membrane formation). In some
embodiments, the surface-active groups are covalently bonded to the
base polymer during synthesis. In some embodiments, surface-active
groups may include silicone, sulfonate, fluorine, polyethylene
oxide, hydrocarbon groups, and the like. The surface activity
(e.g., chemistry, properties) of a membrane domain including a
surface-active group-containing polymer reflects the surface
activity of the surface-active groups rather than that of the base
polymer. In other words, surface-active groups control the
chemistry at the surface (e.g., the biological contacting surface)
of the membrane without compromising the bulk properties of the
base polymer. The surface-active groups of some embodiments are
selected for desirable surface properties, for example,
non-constant noise-blocking ability, break-in time (reduced),
ability to repel charged species, cationic or anionic blocking, or
the like. In some embodiments, the surface-active groups are
located on one or more ends of the polymer backbone, and referred
to as surface-active end groups, wherein the surface-active end
groups are believed to more readily migrate to the surface of the
bioprotective domain/layer formed from the surface-active
group-containing polymer in some circumstances.
[0151] FIG. 4A is a schematic view of a base polymer 400 having
surface-active end groups in one embodiment. In some embodiments,
the surface-active moieties 402 are restricted to the termini of
the linear or branched base polymer(s) 400 such that changes to the
base polymer's bulk properties are minimized. Because the polymers
couple by end groups to the backbone polymer during synthesis, the
polymer backbone retains its strength and processability. The
utility of surface-active end groups is based on their ability to
accumulate at the surface of a formed article made from the
surface-active end group-containing polymer. Such accumulation is
driven by the minimization of interfacial energy of the system,
which occurs as a result of it.
[0152] FIG. 4B is a schematic view of a bioprotective domain,
showing an interface in a biological environment (e.g.,
interstitial space or vascular space). A surface-active
group-containing polymer is shown fabricated as a membrane 46,
wherein the surface-active end groups have migrated to the surface
of the base polymer. While not wishing to be bound by theory, it is
believed that this surface is developed by surface-energy-reducing
migrations of the surface-active end groups to the air-facing
surface during membrane fabrication. It is also believed that the
hydrophobicity and mobility of the end groups relative to backbone
groups facilitate the formation of this uniform over layer by the
surface-active (end) blocks.
[0153] In some embodiments, the bioprotective domain 46 is formed
from a polymer containing silicone as the surface-active group, for
example, a polyurethane containing silicone end group(s). Some
embodiments include a continuous analyte sensor configured for
insertion into a host, wherein the sensor has a membrane located
over the sensing mechanism, which includes a polyurethane
comprising silicone end groups configured to substantially block
the effect of non-constant noise-causing species on the sensor
signal, as described in more detail elsewhere herein. In some
embodiments, the polymer includes about 10%, 11%, 12%, 13%, 14%,
15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%,
28%, 29%, 30%, to about 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,
39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,
52%, 53%, 54% or 55% silicone by weight. In certain embodiments,
the silicone (e.g., a precursor such as PDMS) has a molecular
weight from about 500 to about 10,000 daltons, or in some
embodiments at least about 200 daltons. In some embodiments, the
base polymer includes at least about 10% silicone by weight, for
example from about 19% to about 40% silicone by weight. These
ranges are believed to provide an advantageous balance of
noise-reducing functionality, while maintaining sufficient glucose
permeability in embodiments wherein the sensor is a glucose sensor,
for example.
[0154] In some embodiments, the bioprotective domain is formed from
a polymer containing fluorine as a surface-active group, for
example, a polyurethane that contains a fluorine end groups. In
some embodiments, the polymer includes from about 1% to about 25%
fluorine by weight. Some embodiments include a continuous analyte
sensor configured for insertion into a host, wherein the sensor has
a membrane located over the sensing mechanism, wherein the membrane
includes a polyurethane containing fluorine surface-active groups,
and wherein the membrane is configured and arranged to reduce a
break-in time of a sensor as compared to a membrane formed from a
similar base polymer without the surface-active group(s). For
example, in some preferred embodiments, a glucose sensor having a
bioprotective domain has a response time (e.g., t.sub.90) of less
than 120 seconds, sometimes less than 60 seconds, and sometimes
less than about 45, 30, 20, or 10 seconds (across a physiological
range of glucose concentration).
[0155] In some embodiments, the bioprotective domain may be formed
from a polymer that contains sulfonate as a surface-active group,
for example, a polyurethane containing sulfonate end group(s). In
some embodiments, the continuous analyte sensor configured for
insertion into a host may include a membrane located over the
sensing mechanism, wherein the membrane includes a polymer that
contains sulfonate as a surface-active group, and is configured to
repel charged species, for example, due to the net negative charge
of the sulfonated groups.
[0156] In some embodiments, a blend of two or more (e.g., two,
three, four, five, or more) surface-active group-containing
polymers is used to form a bioprotective membrane domain. For
example, by blending a polyurethane with silicone end groups and a
polyurethane with fluorine end groups, and forming a bioprotective
membrane domain from that blend, a sensor can be configured to
substantially block non-constant noise-causing species and reduce
the sensor's t.sub.90, as described in more detail elsewhere
herein. Similarly, by blending a polyurethane containing silicone
end groups, a polyurethane containing fluorine end groups, and a
polyurethane containing sulfonate end groups, and forming a
bioprotective membrane domain from that blend, a sensor can be
configured to substantially block non-constant noise-causing
species, to reduce the sensor's break-in time and to repel charged
species, as described in more detail above. Although in some
embodiments, blending of two or more surface-active
group-containing polymers is used, in other embodiments, a single
component polymer can be formed by synthesizing two or more
surface-active groups with a base polymer to achieve similarly
advantageous surface properties; however, blending may be
advantageous in some embodiments for ease of manufacture.
Interference Domain
[0157] It is contemplated that in some embodiments, such as in the
sensor configuration illustrated in FIG. 2B, an interference domain
40, also referred to as the interference layer, may be provided in
addition to (or in replacement of) the bioprotective domain. The
interference domain 40 may substantially reduce the permeation of
one or more interferents into the electrochemically reactive
surfaces. The interference domain 40 can be configured to be much
less permeable to one or more of the interferents than to the
measured species. It is also contemplated that in some embodiments,
where interferent blocking may be provided by the bioprotective
domain (e.g., via a surface-active group-containing polymer of the
bioprotective domain), a separate interference domain is not
present. In other embodiments, the membrane includes both an
interference domain and a bioprotective domain, with both domains
configured to reduce the permeation of one or more interferents. In
further embodiments, the interference domain and the bioprotective
domain are each configured to reduce permeation of different
interfering species. For example, the interference domain may have
greater specificity than the bioprotective domain with respect to
reducing permeation of one type of interfering species, while the
bioprotective domain may have greater specificity than the
interference domain with respect to reducing permeation of another
type of interfering species. In some embodiments, both the
interference domain and the bioprotective domain are configured to
target certain interference species for permeation reduction.
[0158] In certain embodiments, the implantable sensor employs a
membrane system comprising a resistance domain, an enzyme domain,
and an interference domain. The interference domain can be proximal
to the sensor and the resistance domain can be distal to the
sensor, with the enzyme domain therebetween. The interference
domain can consist of a single layer or plurality of layers of the
same material. However, in some embodiments, the interference
domain comprises two or more different types of layers in an
alternating configuration. For example, a first type of layer can
be represented by X, a second type of layer can be represented by
Y, and a third type of layer can be represented by Z. The
interference domain including alternating layers can have the
following exemplary configurations:
TABLE-US-00001 XY YX XYX XYXYX XYXYXY XXYYXYXXYY XXXYYYXXXYYYXXX
XYXYXYXYXYXYX XYZXYZXYZX XYXZXYXZXYXZ ZYYXZZZXYYYXZ
[0159] The above configurations, which are merely exemplary,
illustrate various embodiments. In certain embodiments, the first
and last layers are the same (e.g., X and X), in other embodiments,
the first and last layers are different (e.g., X and Y). The domain
can include one or more layers that are unitary (i.e., a single
layer is deposited, e.g., X), or composite (e.g., a first layer of
material is deposited, followed by the deposition of a second and
third, etc. layer of the same material atop the first layer, e.g.,
XXX). The pattern of alternating layers can be regular (e.g.,
XYXYXYXYXY) or irregular (e.g., ZYXZXYZYZ).
[0160] In some embodiments, the alternating layers include
polyanionic layers and polycationic layers. The following are
exemplary interference domain configurations, wherein the
polyanionic layers (unitary, composite, and/or contiguous with the
same polyanion or with different polyanions) are represented by A
and the polycationic layers by C (unitary, composite, and/or
contiguous with the same polyanion or with different
polyanions):
TABLE-US-00002 CA CAC CACA CACAC CACACA CACACAC CACACACA CACACACAC
CACACACACA CACACACACAC CACACACACACA CACACACACACAC CACACACACACACA
CACACACACACACAC CACACACACACACACA CACACACACACACACAC
CACACACACACACACACA CACACACACACACACACAC CACACACACACACACACACA
CACACACACACACACACACAC CACACACACACACACACACACA
CACACACACACACACACACACAC CACACACACACACACACACACACA
CACACACACACACACACACACACAC CACACACACACACACACACACACACAC
CACACACACACACACACACACACACACAC CACACACACACACACACACACACACACACAC
CACACACACACACACACACACACACACACACAC AC ACA ACAC ACACA ACACAC ACACACA
ACACACAC ACACACACA ACACACACAC ACACACACACA ACACACACACAC
ACACACACACACA ACACACACACACAC ACACACACACACACA ACACACACACACACAC
ACACACACACACACACA ACACACACACACACACAC ACACACACACACACACACA
ACACACACACACACACACAC ACACACACACACACACACACA ACACACACACACACACACACAC
ACACACACACACACACACACACA ACACACACACACACACACACACAC
ACACACACACACACACACACACACA ACACACACACACACACACACACACACA
ACACACACACACACACACACACACACACA ACACACACACACACACACACACACACACACA
ACACACACACACACACACACACACACACACACA
[0161] Other configurations (e.g., those including additional
layers, and/or additional materials) are also contemplated for some
embodiments. In some embodiments, each A layer is a unitary or
composite layer of the same polyanion, and each C layer is a
unitary or composite layer of the same polycation. The outermost
layers of the interference domain can both be polycation layers,
with polyanion layers present only as interior layers. Any suitable
number of alternating layers can be employed in the interference
domain, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20 or more bilayers (defined as a polycationic
layer adjacent to a polyanionic layer). In some embodiments a final
polycationic layer is added so as to yield an interference domain
with polycationic layers as the outermost layers. In other
embodiments a final anionic layer is added so as to yield an
interference domain with polyanionic layers as the outermost
layers.
[0162] Polyanions and polycations belong to the class of polymers
commonly referred to as polyelectrolytes--polymers wherein at least
some of the repeating units (or monomers) include one or more ionic
moieties. Polyelectrolytes which bear both cationic and anionic
moieties are commonly referred to as polyampholytes. Certain
polyelectrolytes form self-assembled monolayers wherein one end of
the molecule shows a specific, reversible affinity for a substrate
such that an organized, close-packed monolayer of the
polyelectrolyte can be deposited.
[0163] The polycation can be any biocompatible polycationic
polymer. In some embodiments, the polycation is a biocompatible
water-soluble polycationic polymer. In certain embodiments, water
solubility may be enhanced by grafting the polycationic polymer
with water-soluble polynonionic materials such as polyethylene
glycol. Representative polycationic materials may include, for
example, natural and unnatural polyamino acids having a net
positive charge at neutral pH, positively charged polysaccharides,
and positively charged synthetic polymers. Additional examples of
suitable polycationic materials include polyamines having amine
groups on either the polymer backbone or the polymer sidechains,
such as poly-L-lysine and other positively charged polyamino acids
of natural or synthetic amino acids or mixtures of amino acids,
including poly(D-lysine), poly(ornithine), poly(arginine), and
poly(histidine), and nonpeptide polyamines such as
poly(aminostyrene), poly(aminoacrylate), poly(N-methyl
aminoacrylate), poly(N-ethylaminoacrylate), poly(N,N-dimethyl
aminoacrylate), poly(N,N-diethylaminoacrylate),
poly(diallyldimethyl ammonium chloride), poly(aminomethacrylate),
poly(N-methyl amino-methacrylate), poly(N-ethyl aminomethacrylate),
poly(N,N-dimethyl aminomethacrylate), poly(N,N-diethyl
aminomethacrylate), poly(ethyleneimine), polymers of quaternary
amines, such as poly(N,N,N-trimethylaminoacrylate chloride),
poly(methyacrylamidopropyltrimethyl ammonium chloride), and natural
or synthetic polysaccharides such as chitosan, poly(allylamine
hydrochloride), poly(diallyldimethylammonium chloride),
poly(vinylbenzyltriamethylamine), polyaniline or sulfonated
polyaniline, (p-type doped), polypyrrole (p-type doped),
polyallylamine gluconolactone, and poly(pyridinium acetylene).
[0164] The polyanionic material can be any biocompatible
polyanionic polymer, for example, any polymer having carboxylic
acid groups attached as pendant groups. The polyionic layers can be
hydrophilic (e.g., a material or portion thereof which will more
readily associate with water than with lipids). In some
embodiments, the polyanionic polymer is a biocompatible
water-soluble polyanionic polymer. Suitable materials include, but
are not limited to, alginate, carrageenan, furcellaran, pectin,
xanthan, hyaluronic acid, heparin, heparan sulfate, chondroitin
sulfate, dermatan sulfate, dextran sulfate, polymethacrylic acid,
polyacrylic acid, poly(vinyl sulfate), poly(thiophene-3-acetic
acid), poly(4-styrenesulfonic acid), poly(styrene sulfonate),
(poly[1-[4-(3-carboxy-4-hydroxy-phenylazo)benzene
sulfonamido]-1,2-ethanediyl, sodium
poly(4-[4-({4-[3-amino-2-(4-hydroxy-phenyl)propylcarbamoyl]-5-oxo-pentyl--
}-methyl-amino)-phenylazo]-benzenesulfonic acid), oxidized
cellulose, carboxymethyl cellulose and crosmarmelose, synthetic
polymers, and copolymers containing pendant carboxyl groups, such
as those containing maleic acid or fumaric acid in the backbone.
Polyaminoacids of predominantly negative charge are also suitable.
Examples of these materials include polyaspartic acid, polyglutamic
acid, and copolymers thereof with other natural and unnatural amino
acids. Polyphenolic materials, such as tannins and lignins, can be
used if they are sufficiently biocompatible.
[0165] The molecular weight of the polyionic materials may be
varied in order to alter coating characteristics, such as coating
thickness. As the molecular weight is increased, the coating
thickness generally increases. However, an increase in molecular
weight may result in greater difficulty with handling. To achieve a
balance of coating thickness, material handling, and other design
considerations, the polyionic materials can have a particular
average molecular weight Mn. In some embodiments, the average
molecular weight of a polyionic material used is from about 1,000,
10,000, or 20,000 to about 25,000, 50,000, 100,000 or 150,000
g/mol.
[0166] In some embodiments, the interference domain can be prepared
using a layer-by-layer deposition technique, wherein a substrate
(e.g., the sensor or membrane layer atop the sensor, e.g., the
resistance or enzyme layer) is dipped first in a bath of one
polyelectrolyte, then in a bath of an oppositely charged
polyelectrolyte. Optionally, the substrate can be dipped in a bath
of rinsing solution before or after the substrate is dipped into
the polyelectrolyte bath. During each dip a small amount of
polyelectrolyte is adsorbed and the surface charge is reversed,
thereby allowing a gradual and controlled build-up of
electrostatically cross-linked films (or hydrogen bonded films) of
alternating polycation-polyanion layers. The method provides a
technique for controlling functionality and film thickness and
functionality. For example, it can be employed for depositing films
as thin as one monolayer or for thicker layers. FIG. 9B illustrates
one embodiment of a layer-by-layer deposition method, which employs
alternating adsorption of polycations and polyanions to create a
structure illustrated in FIG. 9A. Operationally, the embodiment
illustrated in FIG. 9B occurs through consecutive exposures of a
substrate 938 to polycation and polyanion solutions, with rinsing
to remove unadsorbed polymer after each deposition step. In a first
step, a polycation 942 is deposited onto a substrate 938 (e.g., a
wire with an electroactive surface or a flat wafer substrate) to
form a polycationic layer 942. As described elsewhere herein in
greater detail, the deposition of the layer can be performed using
any of a variety of techniques, such as, dipping and/or spraying,
for example. In a second step, rinsing is performed to remove
unadsorbed polymer after deposition of the polycationic layer 942.
Next, in a third step, a polyanion 944 is deposited onto the
polycationic layer 942. Thereafter, in a fourth step, rinsing is
performed to remove unadsorbed polymer after deposition of the
polyanionic layer 944. These steps can be repeated until the
desired interference domain configuration and/or structure is
achieved. In an alternative embodiment, instead of depositing a
polycationic layer as the first layer on top of the substrate 938,
a polyanionic layer is deposited instead. Thereafter, a second
layer formed of a polycation is deposited onto the first layer,
i.e., the polyanionic layer. This process is continued until a
certain desired interference domain configuration and/or structure
is achieved.
[0167] In some embodiments, methods can also employ other
interactions such as hydrogen bonding or covalent linkages.
Depending upon the nature of the polyelectrolyte, polyelectrolyte
bridging may occur, in which a single polyelectrolyte chain adsorbs
to two (or more) oppositely charged macroions, thereby establishing
molecular bridges. If only a monolayer of each polyelectrolyte
adsorbs with each deposition step, then electrostatically
cross-linked hydrogel-type materials can be built on a surface a
few microns at a time. If the substrate is not thoroughly rinsed
between the application of polyionic films, thicker, hydrogel-like
structures can be deposited.
[0168] In some embodiments, the interference blocking ability
provided by the alternating polycationic layer(s) and polyanionic
layer(s) can be adjusted and/or controlled by creating covalent
cross-links between the polycationic layer(s) and polyanionic
layer(s). Cross-linking can have a substantial effect on mechanical
properties and structure of the film, which in turn can affect the
film's interference blocking ability. Cross-linked polymers can
have different cross-linking densities. In certain embodiments,
cross-linkers are used to promote cross-linking between layers. In
other embodiments, in replacement of (or in addition to) the
cross-linking techniques described above, heat is used to form
cross-linking. For example, in some embodiments imide and amide
bonds can be formed between a polycationic layer and a polyanionic
layer as a result of high temperature. In some embodiments, photo
cross-linking is performed to form covalent bonds between the
polycationic layers(s) and polyanionic layer(s). One major
advantage to photo-cross-linking is that it offers the possibility
of patterning. In certain embodiments, patterning using photo-cross
linking is performed to modify the film structure and thus to
adjust the interference domain's interference blocking ability.
Blocking ability can correspond to, but is not limited to, the
ability to reduce transport of a certain interfering species or to
the selectivity for the transport of a desired species (e.g.,
H.sub.2O.sub.2) over an interfering species. Post-deposition
reactions, such as cross-linking and reduction of metal ions to
form nanoparticles, provide further ways to modify film properties.
In some embodiments, cross-linking may be performed between
deposition of adjacent polycationic or polyanionic layers in
replacement of (or in addition to) a post-deposition cross-linking
process.
[0169] The overall thickness of the interference layer can impact
its permeability to interferents. The overall thickness of the
interference domain can be controlled by adjusting the number of
layers and/or the degree of rinsing between layers. With layer
deposition through spraying, control of drop size and density can
provide coatings of desired selected thickness without necessarily
requiring rinsing between layers. Additionally, the excess
(unbound) material can be removed via other means, for example, by
an air jet. If the residual polyelectrolyte from the previous layer
is substantially removed before adding the subsequent layer, the
thickness per layer decreases. Accordingly, in one embodiment, the
surface is first coated with a polycation, the excess polycation is
then removed by rinsing the surface, afterwards the polyanion is
added, the excess is then removed, and the process is repeated as
necessary. In some embodiments, the polycations or polyanions from
different adjacent layers may intertwine. In further embodiment,
they may be intertwined over several layers.
[0170] In some embodiments, the level of ionization of polyions may
be controlled, for example, by controlling the pH in the dip
solution comprising the polycation or the polyanion. By changing
the level of ionization of these polyions, the interference
blocking ability of a certain layer of may be altered and/or
controlled. For example, a first polycationic layer that has a
higher level of ionization than a second polycationic layer may be
better at interacting with and reducing the transport a first
interfering species, while the second polycationic may be better at
interacting with and reducing the transport of a second interfering
species. Changes in the level of ionization of a polyion's charge
groups can also affect the mechanical properties, structural
properties, and other certain properties (e.g., diffusion
properties) that may affect the interference domain's ability to
reduce transport of (or entirely block) interfering species. For
example, an alternating bilayer, comprising polycations and
polyanions, both of which have high levels of ionization, may bond
together more tightly than a corresponding bilayer with low levels
of ionization. Thus, the structural difference between these two
membranes, which can be in the form of mechanical properties or
other properties (e.g., thickness of the domain), can affect the
performance of the interference domain.
[0171] In some embodiments, the linear charge density of the
polyelectrolyte may be controlled at least in part by the average
charge spacing along the polyion chain. The spacing between charge
groups on the polycationic and/or polyanionic polymers that form
the interference domain may be controlled by polyelectrolyte
polymer selection or polymer synthesis. How far the charged groups
are spaced can greatly affect the structural properties of the
interference domain. For example, a polyion having charged groups
that are spaced closely to each other may result in small-sized
pores in the interference domain, thereby resulting in a structure
that excludes medium molecular-sized and large molecular-sized
interfering species from passage therethough, while allowing
passage therethrough of small-sized pores. Conversely, a polyion
having charged groups that are spaced apart at a moderate distance
from each other may result in medium-sized pores that exclude large
molecular-sized interfering species and allow passage therethrough
of medium-molecular sized and small molecular-sized interfering
species. In certain embodiments, the linear charge density of the
polyanionic polymer is from about 1 to 50 e/.ANG., sometimes from
about 10 to 25 e/.ANG., sometimes from about 2 to 10 e/.ANG., and
sometimes from 2 to 3 e/.ANG., where e is the elementary charge of
an electron/proton and A is distance in angstroms. In some
embodiments, the linear charge density of the polycationic polymer
is from about 1 to 50 e/.ANG., sometimes from about 10 to 15
e/.ANG., sometimes from about 2 to 10 e/.ANG., and sometimes from 2
to 3 e/.ANG..
[0172] In some embodiments, the linear charge density of
polyanionic polymer is substantially similar to the linear charge
density of the polycationic polymer. For example, in one
embodiment, the polyanionic layer is formed of (i) poly(acrylic
acid), which has an average linear charge density of about 2.5
e/.ANG. and (ii) poly(allylamine hydrochloride), which also has an
average linear charge density of about 2.5 e/.ANG.. In certain
embodiments, the polycationic and polyanionic layers may have an
average linear charge density that is substantially equal with each
other and that is from about 1 to 50 e/.ANG., sometimes from about
2 to 25 e/.ANG., sometimes from about 5 to 10 e/.ANG., other times
from about 10 to 15 e/.ANG., and other times from about 15 to 25
e/.ANG..
[0173] By providing an interference domain with differing linear
charge densities, an interference domain may be formed that
comprises different polycationic/polyanionic bilayers that are
designed specifically to exclude different interfering species
based on certain characteristics (e.g., molecular size) of the
targeted interfering species. For example, in one embodiment, an
outermost bilayer of the interference domain is designed to have a
medium average charge spacing, thereby resulting in a bilayer that
only excludes large molecular-sized species, but allows passage
therethrough of medium molecular-sized species and small
molecular-sized species. Conversely, an innermost bilayer of the
interference domain may be designed to have low average charge
spacing, thereby resulting in a bilayer that excludes all
molecules, except those with very small molecular sizes, for
example, H.sub.2O.sub.2.
[0174] In some embodiments, the polycationic layers may be formed
of the same or substantially the same material (e.g.,
poly(allylamine hydrochloride) (PAH) for polycation or poly(acrylic
acid) (PAA) for polyanion), while having different levels of
ionization. For example, in one embodiment, the interference domain
comprises seven alternating polyelectrolyte layers, with the first,
third, fifth, and seventh layers being polycationic layers, and
with the second, fourth, and sixth layers being polyanionic layers,
wherein the first and seventh layers form the outer layers of the
interference domain. In one embodiment, each or some of the
polycationic layers may have different levels of ionization. For
example, in one embodiment, the first, third, fifth, and seventh
layers may each have different levels of ionization, with the first
layer having the highest level of ionization and the seventh layer
having the lowest level of ionization, or vice versa. In an
alternative embodiment, some of the polycationic layers may share
substantially the same level of ionization. For example, in one
embodiment, the first and seventh layers may have substantially the
same levels of ionization, while the third and fifth layers may
have a level of ionization that is different from the others. As
described elsewhere herein, the ionization level of a polyion may
be controlled by controlling the pH in the dip solution comprising
the polycation or the polyanion. By changing the level of
ionization of these polyions, the interference blocking ability of
a certain layer of may be altered and/or controlled.
[0175] The design of an interference domain having layers with
levels of ionization can also be applied to polyanionic layers as
well. For example, in one embodiment with seven alternating
polyelectrolyte layers, the second, fourth, and sixth layers are
each polyanionic layers and may each have different levels of
ionization, with the second layer having the highest level of
ionization and the sixth layer having the lowest level of
ionization, or vice versa. In an alternative embodiment, some of
the polyanionic layers may share substantially the same level of
ionization. For example, in one embodiment, the second and fourth
layers may have substantially the same levels of ionization, while
the sixth layer may have a substantially different level of
ionization from the others.
[0176] In certain embodiments, the particular polycationic layer(s)
and/or polyanionic layer(s) selected to form the interference layer
may depend at least in part on their ability to block, reduce, or
impede passage therethrough of one or more interferents. For
example, the polyanionic layer can be selected for its ability to
block, reduce, or impede passage of a first interferent, whereas
the polycationic layer is selected for its ability to block,
reduce, or impede passage of a second interferent. The layer may be
designed to slow but not block passage of an interferent
therethrough, or designed to substantially block (e.g., trap) an
interferent therein. Additional polyionic layers can be included in
the interference domain with particular selectivity towards still
different interferents. Depending upon the position of the
interference domain in the membrane system relative to the
electrode or electroactive surface of the sensor, the permeability
of the layer to substances other than the interferent can be
important. In sensor systems wherein H.sub.2O.sub.2 (hydrogen
peroxide) is produced by an enzyme-catalyzed reaction of an analyte
being detected, the interference domain should be designed to allow
H.sub.2O.sub.2 to pass through with minimal impedance if the
interference domain is positioned between the electroactive surface
and the enzyme layer. On the other hand, if in a different membrane
design, the interference domain is positioned distal to the enzyme
layer (with respect to the electroactive surface), then in some
embodiments, the interference domain may be designed to block
H.sub.2O.sub.2 not produced by the enzyme-catalyzed reaction from
passing therethrough. In addition, with this particular membrane
design, the interference domain may be configured to allow analyte
and oxygen to pass therethrough with minimal impedance.
[0177] Application of the layers in forming the interference domain
may be accomplished by various methods known in the art. One
coating process embodiment involves solely dip-coating and
dip-rinsing steps. Another coating process embodiment involves
solely spray-coating and spray-rinsing steps. However, a number of
alternative embodiments involve various use of a combination of
spray-coating, dip-coating, and/or rinsing steps. For example, one
dip-coating method involves the steps of applying a coating of a
first polyionic material to a substrate (e.g., the sensor or
membrane layer atop the sensor, e.g., the resistance or enzyme
layer) by immersing the substrate in a first solution of a first
polyionic material; rinsing the substrate by immersing the
substrate in a rinsing solution; and, optionally, drying the
substrate. This procedure is then repeated using a second polyionic
material, with the second polyionic material having charges
opposite of the charges of the first polyionic material, in order
to form a polyionic bilayer. This bilayer formation process can be
repeated a plurality of times in order to produce the interference
domain. In some embodiments, the number of bilayers can be from 1
to about 16 bilayers, sometimes from 1 to about 10 bilayers, and
sometimes from about 3 to about 7 bilayers. In certain embodiments,
the final layer of oppositely charged polyionic material can be
deposited, such that the first and the last layer have the same
charges (both positive, or both negative). The immersion time for
each of the coating and rinsing steps may vary depending on a
number of factors. For example, immersion of the substrate into the
polyionic solution can occur over a period of about 1 to 30
minutes, or from about 2 to 20 minutes, or from about 1 to 5
minutes. Rinsing may be accomplished in one step, but a plurality
of rinsing steps can also be employed. Rinsing in a series from
about 2 to 5 steps can be employed, with each immersion into the
rinsing solution consuming, for example, from about 1 to about 3
minutes. In some embodiments, several polycationic solutions and/or
several polyanion solutions may be used. For example, in certain
embodiments, the dip-coating sequence may involve the steps of
applying a coating of a first polycationic material to the
substrate to form a first layer, then applying a first anionic
material to the first layer to form a second layer, then applying a
second polycationic material to the second layer to form a third
layer, then applying a second polyanionic material to form a fourth
layer, and then applying a first or second polycationic material to
the fourth layer to form a fifth layer. In some of these
embodiments, the dip-coating sequence described above may be
interspersed with rinsing steps performed between coating steps. It
is contemplated that any of a variety of permutations involving the
steps and materials described may be employed. In alternative
embodiments, the materials used to form the polycationic and/or
polyanionic layers may be substantially the same. However, the
individual polycationic layers may have a different level of
ionization than one or more other polycationic layers in the
inference domain, and the individual polyanionic layers may also
have a different level of ionization than one or more other
polyanionic layers. For example, in one embodiment, the dip-coating
sequence method involves the use of a first solution at a first pH
comprising a polycationic material, a second solution at a second
pH comprising a polyanionic material, a third solution at a third
pH comprising the aforementioned polycationic material, a fourth
solution at a fourth pH comprising the aforementioned polyanionic
material, and a fifth solution at a fifth pH comprising the
aforementioned polycationic material. Even though the same
polycationic material is used to form the first, third, and fifth
layers, because the solution used to form the first, third, and
fifth layers have different pHs, the ionization levels of the
first, third, and fifth layers will be different. Likewise, even
though the same polyanionic material is used to form the second and
fourth layers, because the solution used to form the second and
fifth layers have different pHs, the levels of ionization of the
second and fourth layers will be different. This difference in
ionization levels can affect, inter alia, the mechanical properties
of the film, structural properties (e.g., porosity, roughness) of
the film, diffusional properties of the film, and also the
selectivity of a certain polyelectrolyte layer for a certain
interfering species over another interfering species. All of these
effects influence the ability of the individual polyelectrolyte
layers and of the interference domain to reduce transport of a
variety of interfering species. In certain embodiments, at least
two polycationic and/or two polyanionic layers of the interference
domain are formed from the same polycationic/polyanionic material,
but through use of solutions at different pHs. In some of these
embodiments, a first polycationic layer possesses a high
selectivity for a particular interfering species over other
interfering species, while a second polycationic layer possesses a
high selectivity for a different interfering species over other
interfering species.
[0178] Alternatively or additionally, spray coating techniques can
be employed. In one embodiment, the coating process generally
includes the steps of applying a coating of: a first polyionic
material to the substrate by contacting the substrate with a first
solution of a first polyionic material; rinsing the substrate by
spraying the substrate with a rinsing solution; and (optionally)
drying the substrate. Similar to the dip-coating process, the
spray-coating process may then be repeated with a second polyionic
material, with the second polyionic material having charges
opposite to those of the first polyionic material. The contacting
of the substrate with solution, either polyionic material or
rinsing solution, may occur through a variety of methods. For
example, the substrate may be dipped into both solutions. One
alternative is to apply the solutions in a spray or mist form. Of
course, various combinations are possible and within the scope of
the contemplated embodiments, e.g., dipping the substrate in the
polyionic material followed by spraying the rinsing solution. The
spray coating application may be accomplished via a number of
methods known in the art. For example, a conventional spray coating
arrangement may be used, i.e., the liquid material is sprayed by
application of fluid, which may or may not be at an elevated or
lowered pressure, through a reduced diameter nozzle which is
directed towards the deposition target. Another spray coating
technique involves the use of ultrasonic energy, whereby the liquid
is atomized by the ultrasonic vibrations of a spray forming tip and
thereby changed to a spray.
[0179] Yet another technique involves electrostatic spray coating
in which a charge is conveyed to the fluid or droplets to increase
the efficiency of the coating. A further method of atomizing liquid
for spray coating involves purely mechanical energy, e.g., through
contacting the liquid with a high speed reciprocating member or a
high speed rotating disk. Still another method of producing
microdroplets for spray coatings involves the use of piezoelectric
elements to atomize the liquid. These techniques can be employed
with air assistance or at an elevated solution pressure. In
addition, a combination of two or more techniques may prove more
useful with certain materials and conditions. A method of spray
application involves dispensing, with a metering pump, the
polyanion or polycation solution to an ultrasonic dispensing head.
The polyion layer is sprayed so as to allow the surface droplets to
coalesce across the material surface. The resulting layer may then
be allowed to interact for a period of time or immediately rinsed
with water or saline solution (or other solution devoid of
polyanion or polycation).
[0180] In some embodiments, the layers of the interference domain
can include a polymer with a conjugated pi system. Polymers with
conjugated pi systems can contain a delocalized electron system,
and can be conductive. Layers of polymers with conjugated pi
systems can interact with each other through intermolecular forces,
such as electrostatic pi-pi interactions (i.e., pi-stacking).
Conjugated polymers can provide beneficial properties to an
interference domain, such as increasing the rigidity, integrity,
and/or reproducibility of the domain. In some embodiments, the
polymer with a conjugated pi system can be polyacetylene,
polypyrrole, polythiophene, poly(p-phenylene),
poly(p-phenylenevinylene) or poly(carbazole). The interference
domain can include alternating layers of any of the conjugated
polymers mentioned above. In some embodiments, the number of layers
of conjugated polymers can be from 1 to about 20 layers, sometimes
from about 3 to about 10 layers.
[0181] It is contemplated that in some embodiments, the thickness
of the interference domain may be from about 0.01 microns or less
to about 20 microns or more. In some of these embodiments, the
thickness of the interference domain may be from about 0.01, 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. In some of these embodiments, the
thickness of the interference domain may be from about 0.2, 0.4,
0.5, or 0.6, microns to about 0.8, 0.9, 1, 1.5, 2, 3, or 4
microns.
[0182] Polyimine Films
[0183] In some embodiments, certain polymeric films can be used to
form interference domains. For example, certain polyimides prepared
from 2,2'-dimethyl-4,4'-diaminobiphenyl and the corresponding
dianhydride can be cast into films that can be employed as hydrogen
peroxide-selective membranes. See, e.g., Ekinci et al., Turk. J.
Chem. (2006), 277-285. In one embodiment, a film is prepared using
the following steps. First, n-methyl-2-pyrrolidene (NMP) is
distilled over CaH.sub.2 under reduced pressure and is stored over
about 4 .ANG. molecular sieves. Reagent grade pyromellitic
dianhydride (PMDA) is sublimed at about 250.degree. C. under
reduced pressure and dried under vacuum at about 120.degree. C.
prior to use. The diamine is purified via recrystallization from
ethanol to give shiny crystals. Next,
2,20-dimethyl-4,40-diaminobiphenyl, (about 1.06 g, about 5 mmol) is
dissolved in NMP (about 15 mL) in a 50 mL Schlenk tube equipped
with a nitrogen line, overhead stirrer, a xylene filled Dean-Stark
trap, and a condenser. PMDA (about 1.09 g, about 5 mmol) is then
added to the amine solution, followed by overnight stirring
resulting in a viscous solution. After being stirred for about 3
hours, the solution is heated to reflux at about 200.degree. C. for
about 15 hours. During the polymerization process, the water
generated from the imidization is allowed to distill from the
reaction mixture together with about 1-2 mL of xylene. After being
allowed to cool to ambient temperature, the solution is diluted
with NMP and then slowly added to a vigorously stirred solution of
95% ethanol. The precipitated polymer is collected via filtration,
washed with ethanol, and dried under reduced pressure at
150.degree. C. Before coating, a substrate (e.g., Pt electrode) is
cleaned and optionally polished with aqueous alumina slurry down to
about 0.05 Then about 20 .mu.L of polymer solution prepared by
dissolving about 70 mg of polyimide in about 2 mL of NMP is dropped
onto the surface of the Pt electrode and allowed to dry at room
temperature for about 3 days.
[0184] Self Assembly Techniques
[0185] A self-assembly process can be employed to build up
ultrathin multilayer films comprising consecutively alternative
anionic and cationic polyelectrolytes on a charged surface. See,
e.g., Decher et al., Thin Solid Films, 210-211 (1992) 831-835.
Ionic attraction between opposite charges is the driving force for
the multilayer buildup. In contrast to chemisorption techniques
that require a reaction yield of about 100% in order to maintain
surface functional density in each layer, no covalent bonds need to
be formed with a self-assembly process. Additionally, an advantage
over the classic Langmuir-Blodgett technique is that a solution
process is independent of the substrate size and topology.
Exemplary polyelectrolytes for use in such a process include, but
are not limited to, polystyrenesulfonate sodium salt,
polyvinylsulfate potassium salt,
poly-4-vinylbenzyl-(N,N-diethyl-N-methyl-)-ammonium iodide, and
poly(allylamine hydrochloride). The buildup of multilayer films can
be conducted as follows. A solid substrate with a positively
charged planar surface is immersed in the solution containing the
anionic polyelectrolyte and a monolayer of the polyanion is
adsorbed. Since the adsorption is carried out at relatively high
concentrations of polyelectrolyte, a number of ionic groups remain
exposed to the interface with the solution and thus the surface
charge is reversed. After rinsing in pure water the substrate is
immersed in the solution containing the cationic polyelectrolyte.
Again a monolayer is adsorbed but now the original surface charge
is restored. By repeating both steps in a cyclic fashion,
alternating multilayer assemblies of both polymers are obtained.
This process of multilayer formation is based on the attraction of
opposite charges, and thus requires a minimum of two oppositely
charged molecules. Consequently, one is able to incorporate more
than two molecules into the multilayer, simply by immersing the
substrate in as many solutions of polyeletrolytes as desired, as
long as the charge is reversed from layer to layer. Even aperiodic
multilayer assemblies can easily be prepared. In this respect, the
technique is more versatile than the Langmuir-Blodgett technique
which is rather limited to periodically alternating layer systems.
Another advantage is that the immersion procedure does not pose
principal restrictions as to the size of the substrate or to the
automation in a continuous process.
[0186] Specific examples of the preparation of such films are as
follows. Polystyrenesulfonate (sodium salt, Mr=100,000) and
polyvinylsulfate (potassium salt, Mr=245,000) and poly(allylamine
hydrochloride), Mw=50,000-65,000) are obtained from commercial
sources and employed without further purification.
Poly-4-vinylbenzyl-(N,N-diethyl-N-methyl-)-ammonium iodide can be
synthesized, as described in Decher et al., Ber. Bunsenges. Phys.
Chem., 95 (1992) 1430. Alternating multilayer assemblies of all
materials can be characterized by UV/vis spectroscopy and small
angle X-ray scattering (SAXS) using techniques known in the art.
Direct-light microscopy and SAXS measurements can be performed with
multilayer assemblies on suitable substrates. The multilayer films
can be deposited on, e.g., atop a platinum electrode or other metal
electrode, or a suitable intervening layer atop an electrode. For
the adsorption of the first layer, an aqueous acidic solution of
polystyrenesulfonate or polyvinylsulfate can be used. Afterwards
the substrate is rinsed with water. After the adsorption of the
first layer, the substrates can be stored for some weeks without
noticeable deterioration of the surface. Thereafter, the cationic
polyelectrolyte polyallylamine is adsorbed from aqueous solution.
In the case of the non-quarternized polyallylamine, the polycation
is adsorbed from an acidic solution. All following layers (odd
layer numbers) of the anionic polyelectrolytes are adsorbed from
aqueous solution. In the case of samples containing polyallylamine
as the previously adsorbed layer, polystyrenesulfonate layers can
be adsorbed from an acidic solution. An adsorption time of about 20
minutes at ambient temperature can be employed, however, in certain
embodiments longer or shorter adsorption times may be acceptable. A
range of polymer concentrations (e.g., 20 to 30 mg per about 10 ml
water) can provide acceptable results.
[0187] Multilayer molecular films of polyelectrolyte:calixarene and
polyelectrolyte:cyclodextrin hosts can be fabricated by alternating
adsorption of charged species in aqueous solutions onto a suitable
substrate. See, e.g., X. Yang, Sensors and Actuators B 45 (1997)
87-92. Such a layer-by-layer molecular deposition approach can be
used to integrate molecular recognition reagents into polymer
films. The deposition process is highly reproducible and the
resulting films are uniform and stable. Replacing polyanions,
highly negatively charged molecular species can be used for film
fabrication. These molecular reagents are capable of binding
organic species and can be deposited as functional components into
thin films. This approach incorporates polymer and molecular
elements into the film and thus results in films with polymer's
physical properties and molecular film's selectivity. Films can be
prepared as follows. The substrate (e.g., Pt electrode) can be
first treated with aminopropyltrimethoxysilane in chloroform,
followed with deposition of PSS and then PDDA polyelectrolytes by
dipping into the aqueous solutions of the polyelectrolytes,
respectively. After this, alternating depositions of negatively
charged molecular host species (e.g., calix[6]arene or
p-t-butylcalix[4]arene) and PDDA can be carried out until the
desired number of bilayers is reached. Between each deposition, the
substrate is thoroughly rinsed with deionized water. The
polyelectrolyte and molecular ion assembly can be monitored by
UV-vis absorption spectroscopy and mass loading can be measured
with surface acoustic wave (SAW) devices.
[0188] Polyurethane Membranes
[0189] Hydrophobic-hydrophilic copolymer films such as are
described in U.S. Patent Publication No. US-2006-0086624-A1 can
advantageously be employed in sensors of preferred embodiments.
Films comprising the copolymer can be prepared as follows. A
coating solution is prepared by placing approximately 281 gm of
dimethylacetamide (DMAC) into a 3 L stainless steel bowl to which a
solution of polyetherurethaneurea (344 gm of Chronothane H
(Cardiotech International, Inc., Woburn, Mass.), 29,750 cp @ 25%
solids in DMAC) is added. To this mixture is added another
polyetherurethaneurea (approximately 312 gm, Chronothane 1020
(Cardiotech International, Inc., Woburn, Mass.), 6275 cp @ 25%
solids in DMAC). The bowl is then fitted to a planetary mixer with
a paddle-type blade and the contents are stirred for 30 minutes at
room temperature. Coatings solutions prepared in this manner are
then coated at between room temperature to about 70.degree. C. onto
a substrate, e.g., using a knife-over-roll set at a 0.012 inch gap.
The film is continuously dried at 120.degree. C. to about
150.degree. C. The final film thickness is approximately 0.0015
inches.
Membrane Fabrication
[0190] Polymers of the various embodiments may be processed by
solution-based techniques such as spraying, dipping, casting,
electrospinning, vacuum deposition, vapor deposition, spin coating,
and the like. Water-based polymer emulsions can be fabricated to
form membranes by methods similar to those used for solvent-based
materials. In both cases, the evaporation of a volatile liquid
(e.g. organic solvent or water) leaves behind a film of the
polymer. Cross-linking of the deposited film may be performed
through the use of multi-functional reactive ingredients by a
number of methods well known to those skilled in the art. The
liquid system may cure by heat, moisture, high-energy radiation,
ultraviolet light, or by completing the reaction, which produces
the final polymer in a mold or on a substrate to be coated.
[0191] Domains that include at least two surface-active
group-containing polymers may be made using any of the methods of
forming polymer blends known in the art. In one exemplary
embodiment, a solution of a polyurethane containing silicone end
groups is mixed with a solution of a polyurethane containing
fluorine end groups (e.g., wherein the solutions include the
polymer dissolved in a suitable solvent such as acetone, ethyl
alcohol, DMAC, THF, 2-butanone, and the like). The mixture can then
be drawn into a film or applied to a surface using any method known
in the art (e.g., spraying, painting, dip coating, vapor
depositing, molding, 3-D printing, lithographic techniques (e.g.,
photolithograph), micro- and nano-pipetting printing techniques,
etc.). The mixture can then be cured under high temperature (e.g.,
at about 50-150.degree. C.). Other suitable curing methods may
include ultraviolet or gamma radiation, for example.
[0192] Some amount of cross-linking agent can also be included in
the mixture to induce cross-linking between polymer molecules.
Non-limiting examples of suitable cross-linking agents include
isocyanate, carbodiimide, gluteraldehyde or other aldehydes, epoxy,
acrylates, free-radical based agents, ethylene glycol diglycidyl
ether (EGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), or
dicumyl peroxide (DCP). In one embodiment, from about 0.1% to about
15% w/w of cross-linking agent is added relative to the total dry
weights of cross-linking agent and polymers added when blending the
ingredients (in one example, about 1% to about 10%). During the
curing process, substantially all of the cross-linking agent is
believed to react, leaving substantially no detectable unreacted
cross-linking agent in the final film.
[0193] In some embodiments, the bioprotective domain 46 is
positioned most distally to the sensing region such that its outer
most domain contacts a biological fluid when inserted in vivo. In
some embodiments, the bioprotective domain is resistant to cellular
attachment, impermeable to cells, and may be composed of a
biostable material. While not wishing to be bound by theory, it is
believed that when the bioprotective domain 46 is resistant to
cellular attachment (for example, attachment by inflammatory cells,
such as macrophages, which are therefore kept a sufficient distance
from other domains, for example, the enzyme domain), hypochlorite
and other oxidizing species are short-lived chemical species in
vivo, and biodegradation does not generally occur. Additionally,
the materials for forming the bioprotective domain 46 may be
resistant to the effects of these oxidative species and have thus
been termed biodurable. In some embodiments, the bioprotective
domain controls the flux of oxygen and other analytes (for example,
glucose) to the underlying enzyme domain (e.g., wherein the
functionality of the diffusion resistance domain is built-into the
bioprotective domain such that a separate diffusion resistance
domain is not required).
[0194] In certain embodiments, the thickness of the bioprotective
domain may be from about 0.1, 0.5, 1, 2, 4, 6, 8 microns or less to
about 10, 15, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200 or 250
microns or more. In some of these embodiments, the thickness of the
bioprotective domain may be sometimes from about 1 to about 5
microns, and sometimes from about 2 to about 7 microns. In other
embodiments, the bioprotective domain may be from about 20 or 25
microns to about 50, 55, or 60 microns thick. In some embodiments,
the glucose sensor may be configured for transcutaneous or
short-term subcutaneous implantation, and may have a thickness from
about 0.5 microns to about 8 microns, and sometimes from about 4
microns to about 6 microns. In one glucose sensor configured for
fluid communication with a host's circulatory system, the thickness
may be from about 1.5 microns to about 25 microns, and sometimes
from about 3 to about 15 microns. It is also contemplated that in
some embodiments, the bioprotective layer or any other layer of the
electrode may have a thickness that is consistent, but in other
embodiments, the thickness may vary. For example, in some
embodiments, the thickness of the bioprotective layer may vary
along the longitudinal axis of the electrode end.
Diffusion Resistance Domain
[0195] In some embodiments, a diffusion resistance domain 44, also
referred to as a diffusion resistance layer, may be used and is
situated more proximal to the implantable device relative to the
bioprotective domain. In some embodiments, the functionality of the
diffusion resistance domain may be built into the bioprotective
domain that comprises the surface-active group-containing base
polymer. Accordingly, it is to be noted that the description herein
of the diffusion resistance domain may also apply to the
bioprotective domain. The diffusion resistance domain serves to
control the flux of oxygen and other analytes (for example,
glucose) to the underlying enzyme domain. As described in more
detail elsewhere herein, there exists a molar excess of glucose
relative to the amount of oxygen in blood, i.e., 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 sensor
employing oxygen as cofactor is supplied with oxygen in
non-rate-limiting excess in order to respond linearly to changes in
glucose concentration, while not responding to changes in oxygen
tension. More 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 up
to about 40 mg/dL. However, in a clinical setting, a linear
response to glucose levels is desirable up to at least about 500
mg/dL.
[0196] The diffusion resistance domain 44 includes a semipermeable
membrane that controls the flux of oxygen and glucose to the
underlying enzyme domain 44, which can optionally render oxygen in
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 diffusion resistance domain. In some
embodiments, the diffusion resistance domain exhibits an
oxygen-to-glucose permeability ratio of approximately 200:1, but in
other embodiments the oxygen-to-glucose permeability ratio may be
approximately 100:1, 125:1, 130:1, 135:1, 150:1, 175:1, 225:1,
250:1, 275:1, 300:1, or 500:1. As a result of the high
oxygen-to-glucose permeability ratio, one-dimensional reactant
diffusion may provide sufficient excess oxygen at all reasonable
glucose and oxygen concentrations found in the subcutaneous matrix
(See Rhodes et al., Anal. Chem., 66:1520-1529 (1994)). In some
embodiments, a lower ratio of oxygen-to-glucose can be sufficient
to provide excess oxygen by using a high oxygen soluble domain (for
example, a silicone material) to enhance the supply/transport of
oxygen to the enzyme membrane or electroactive surfaces. By
enhancing the oxygen supply through the use of a silicone
composition, for example, glucose concentration can be less of a
limiting factor. In other words, if more oxygen is supplied to the
enzyme or electroactive surfaces, then more glucose can also be
supplied to the enzyme without creating an oxygen rate-limiting
excess.
[0197] In some embodiments, the diffusion resistance domain is
formed of a base polymer synthesized to include a polyurethane
membrane with both hydrophilic and hydrophobic regions to control
the diffusion of glucose and oxygen to an analyte sensor. A
suitable hydrophobic polymer component may be a polyurethane or
polyether urethane urea. Polyurethane is a polymer produced by the
condensation reaction of a diisocyanate and a difunctional
hydroxyl-containing material. A polyurea is a polymer produced by
the condensation reaction of a diisocyanate and a difunctional
amine-containing material. 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 various embodiments. The material that forms the basis
of the hydrophobic matrix of the diffusion 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.
[0198] In one embodiment of a polyurethane-based resistance domain,
the hydrophilic polymer component is polyethylene oxide. For
example, one useful 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.
[0199] Alternatively, in some embodiments, the resistance domain
may comprise a combination of a base polymer (e.g., polyurethane)
and one or more hydrophilic polymers (e.g., PVA, PEG,
polyacrylamide, acetates, PEO, PEA, PVP, and variations thereof).
It is contemplated that any of a variety of combination of polymers
may be used to yield a blend with desired glucose, oxygen, and
interference permeability properties. For example, in some
embodiments, the resistance domain may be formed from a blend of a
silicone polycarbonate-urethane base polymer and a PVP hydrophilic
polymer, but in other embodiments, a blend of a polyurethane, or
another base polymer, and one or more hydrophilic polymers may be
used instead. In some of the embodiments involving the use of PVP,
the PVP portion of the polymer blend may comprise from about 5% to
about 50% by weight of the polymer blend, sometimes from about 15%
to 20%, and other times from about 25% to 40%. It is contemplated
that PVP of various molecular weights may be used. For example, in
some embodiments, the molecular weight of the PVP used may be from
about 25,000 daltons to about 5,000,000 daltons, sometimes from
about 50,000 daltons to about 2,000,000 daltons, and other times
from 6,000,000 daltons to about 10,000,000 daltons.
[0200] In some embodiments, the diffusion resistance domain 44 can
be formed as a unitary structure with the bioprotective domain 46;
that is, the inherent properties of the diffusion resistance domain
44 are incorporated into bioprotective domain 46 such that the
bioprotective domain 46 functions as a diffusion resistance domain
44.
[0201] In certain embodiments, the thickness of the resistance
domain may be from about 0.05 microns or less to about 200 microns
or more. In some of these embodiments, the thickness of the
resistance domain may be 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, 3.5, 4, 6, 8 microns
to about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30,
40, 50, 60, 70, 75, 80, 85, 90, 95, or 100 microns. In some
embodiments, the thickness of the resistance domain is from about
2, 2.5, or 3 microns to about 3.5, 4, 4.5, or 5 microns in the case
of a transcutaneously implanted sensor or from about 20 or 25
microns to about 40 or 50 microns in the case of a wholly implanted
sensor.
Enzyme Domain
[0202] In some embodiments, an enzyme domain 42, also referred to
as the enzyme layer, may be used and is situated less distal from
the electrochemically reactive surfaces than the diffusion
resistance domain 44. The enzyme domain comprises a catalyst
configured to react with an analyte. In one embodiment, the enzyme
domain is an immobilized enzyme domain 42 including glucose
oxidase. In other embodiments, the enzyme domain 42 can be
impregnated with other oxidases, for example, galactose oxidase,
cholesterol oxidase, amino acid oxidase, alcohol oxidase, lactate
oxidase, or uricase. For example, for an enzyme-based
electrochemical glucose sensor to perform well, the sensor's
response should neither be limited by enzyme activity nor cofactor
concentration.
[0203] In some embodiments, the catalyst (enzyme) can be
impregnated or otherwise immobilized into the bioprotective or
diffusion resistance domain such that a separate enzyme domain 42
is not required (e.g., wherein a unitary domain is provided
including the functionality of the bioprotective domain, diffusion
resistance domain, and enzyme domain). In some embodiments, the
enzyme domain 42 is formed from a polyurethane, for example,
aqueous dispersions of colloidal polyurethane polymers including
the enzyme.
[0204] In some embodiments, the thickness of the enzyme domain may
be from about 0.01, 0.05, 0.6, 0.7, or 0.8 microns to about 1, 1.2,
1.4, 1.5, 1.6, 1.8, 2, 2.1, 2.2, 2.5, 3, 4, 5, 10, 20, 30 40, 50,
60, 70, 80, 90, or 100 microns. In some embodiments, the thickness
of the enzyme domain is between 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, 4, or 5 microns and
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 25,
or 30 microns. In some embodiments, the thickness of the enzyme
domain is from about 2, 2.5, or 3 microns to about 3.5, 4, 4.5, or
5 microns in the case of a transcutaneously implanted sensor or
from about 6, 7, or 8 microns to about 9, 10, 11, or 12 microns in
the case of a wholly implanted sensor.
Electrode Domain
[0205] It is contemplated that in some embodiments, such as the
embodiment illustrated in FIG. 2C, an optional electrode domain 36,
also referred to as the electrode layer, may be provided, in
addition to the bioprotective domain and the enzyme domain;
however, in other embodiments, the functionality of the electrode
domain may be incorporated into the bioprotective domain so as to
provide a unitary domain that includes the functionality of the
bioprotective domain, diffusion resistance domain, enzyme domain,
and electrode domain. In some embodiments, the electrode domain may
be replaced by an interference domain. In other embodiments,
however, the membrane can include both an interference domain and
an electrode domain.
[0206] In some embodiments, the electrode domain is located most
proximal to the electrochemically reactive surfaces. To facilitate
electrochemical reaction, the electrode domain may include a
semipermeable coating that maintains hydrophilicity at the
electrochemically reactive surfaces of the sensor interface. The
electrode domain can enhance the stability of an adjacent domain by
protecting and supporting the material that makes up the adjacent
domain. The electrode domain may also assist in stabilizing the
operation of the device by overcoming electrode start-up problems
and drifting problems caused by inadequate electrolyte. The
buffered electrolyte solution contained in the electrode domain may
also protect against pH-mediated damage that can result from the
formation of a large pH gradient between the substantially
hydrophobic interference domain and the electrodes due to the
electrochemical activity of the electrodes.
[0207] In some embodiments, the electrode domain includes a
flexible, water-swellable, substantially solid gel-like film (e.g.,
a hydrogel) having a `dry film` thickness of from about 0.05
microns to about 100 microns, and sometimes from about 0.05, 0.1,
0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 1 microns to about 1.5,
2, 2.5, 3, or 3.5, 4, 4.5, 5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10,
10.5, 11, 11.5, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 30, 40,
50, 60, 70, 80, 90, or 100 microns. In some embodiments, the
thickness of the electrode domain may be from about 2, 2.5, or 3
microns to about 3.5, 4, 4.5, or 5 microns in the case of a
transcutaneously implanted sensor, or from about 6, 7, or 8 microns
to about 9, 10, 11, or 12 microns in the case of a wholly implanted
sensor. The term `dry film thickness` 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 thickness of a cured film cast from a coating formulation onto
the surface of the membrane by standard coating techniques. The
coating formulation may comprise a premix of film-forming polymers
and a cross-linking agent and may be curable upon the application
of moderate heat.
[0208] In certain embodiments, the electrode domain may be formed
of a curable mixture of a urethane polymer and a hydrophilic
polymer. In some of these embodiments, coatings are formed of a
polyurethane polymer having anionic carboxylate functional groups
and non-ionic hydrophilic polyether segments, which are
cross-linked in the presence of polyvinylpyrrolidone and cured at a
moderate temperature of about 50.degree. C.
[0209] Particularly suitable for this purpose are aqueous
dispersions of fully-reacted colloidal polyurethane polymers having
cross-linkable carboxyl functionality (e.g., BAYBOND.RTM.; Mobay
Corporation). These polymers are supplied in dispersion grades
having a polycarbonate-polyurethane backbone containing carboxylate
groups identified as W-121 and W-123; and a polyester-polyurethane
backbone containing carboxylate groups, identified as W-110-2. In
some embodiments, BAYBOND.RTM. 123, an aqueous anionic dispersion
of an aliphatic polycarbonate urethane polymer sold as a 35 weight
percent solution in water and co-solvent N-methyl-2-pyrrolidone,
may be used.
[0210] In some embodiments, the electrode domain is formed from a
hydrophilic polymer that renders the electrode domain substantially
more hydrophilic than an overlying domain (e.g., interference
domain, enzyme domain). Such hydrophilic polymers may include, a
polyamide, a polylactone, a polyimide, a polylactam, a
functionalized polyamide, a functionalized polylactone, a
functionalized polyimide, a functionalized polylactam or
combinations thereof, for example.
[0211] In some embodiments, the electrode domain is formed
primarily from a hydrophilic polymer, and in some of these
embodiments, the electrode domain is formed substantially from PVP.
PVP is a hydrophilic water-soluble polymer and is available
commercially in a range of viscosity grades and average molecular
weights ranging from about 18,000 to about 500,000, under the PVP
homopolymer series by BASF Wyandotte and by GAF Corporation. In
certain embodiments, a PVP homopolymer having an average molecular
weight of about 360,000 identified as PVP-K90 (BASF Wyandotte) may
be used to form the electrode domain. Also suitable are
hydrophilic, film-forming copolymers of N-vinylpyrrolidone, such as
a copolymer of N-vinylpyrrolidone and vinyl acetate, a copolymer of
N-vinylpyrrolidone, ethylmethacrylate and methacrylic acid
monomers, and the like.
[0212] In certain embodiments, the electrode domain is formed
entirely from a hydrophilic polymer. Useful hydrophilic polymers
contemplated include, but are not limited to,
poly-N-vinylpyrrolidone, poly-N-vinyl-2-piperidone,
poly-N-vinyl-2-caprolactam, poly-N-vinyl-3-methyl-2-caprolactam,
poly-N-vinyl-3-methyl-2-piperidone,
poly-N-vinyl-4-methyl-2-piperidone,
poly-N-vinyl-4-methyl-2-caprolactam,
poly-N-vinyl-3-ethyl-2-pyrrolidone,
poly-N-vinyl-4,5-dimethyl-2-pyrrolidone, polyvinylimidazole,
poly-N,N-dimethylacrylamide, polyvinyl alcohol, polyacrylic acid,
polyethylene oxide, poly-2-ethyl-oxazoline, copolymers thereof and
mixtures thereof. A blend of two or more hydrophilic polymers may
be used in some embodiments.
[0213] It is contemplated that in certain embodiments, the
hydrophilic polymer used may not be cross-linked, but in other
embodiments, cross-linking may be used and achieved by any of a
variety of methods, for example, by adding a cross-linking agent.
In some embodiments, a polyurethane polymer may be cross-linked in
the presence of PVP by preparing a premix of the polymers and
adding a cross-linking agent just prior to the production of the
membrane. Suitable cross-linking agents contemplated include, but
are not limited to, carbodiimides (e.g.,
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride,
UCARLNK.RTM.. XL-25 (Union Carbide)), epoxides and
melamine/formaldehyde resins. Alternatively, it is also
contemplated that cross-linking may be achieved by irradiation at a
wavelength sufficient to promote cross-linking between the
hydrophilic polymer molecules, which is believed to create a more
tortuous diffusion path through the domain.
[0214] The flexibility and hardness of the coating can be varied as
desired by varying the dry weight solids of the components in the
coating formulation. The term `dry weight solids` 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 dry weight percent based on the total coating composition
after the time the cross-linker is included. In one embodiment, a
coating formulation can contain about 6 to about 20 dry weight
percent, such as about 8 dry weight percent, PVP; about 3 to about
10 dry weight percent, sometimes about 5 dry weight percent
cross-linking agent; and about 70 to about 91 weight percent,
sometimes about 87 weight percent of a polyurethane polymer, such
as a polycarbonate-polyurethane polymer, for example. The reaction
product of such a coating formulation is referred to herein as a
water-swellable cross-linked matrix of polyurethane and PVP.
[0215] In some embodiments, underlying the electrode domain is an
electrolyte phase that when hydrated is a free-fluid phase
including a solution containing at least one compound, typically a
soluble chloride salt, which conducts electric current. In one
embodiment wherein the membrane system is used with a glucose
sensor such as is described herein, the electrolyte phase flows
over the electrodes and is in contact with the electrode domain. It
is contemplated that certain embodiments may use any suitable
electrolyte solution, including standard, commercially available
solutions. Generally, the electrolyte phase can have the same
osmotic pressure or a lower osmotic pressure than the sample being
analyzed. In some embodiments, the electrolyte phase comprises
normal saline.
Bioactive Agents
[0216] It is contemplated that any of a variety of bioactive
(therapeutic) agents can be used with the analyte sensor systems
described herein, such as the analyte sensor system shown in FIG.
1. In some embodiments, the bioactive 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 these embodiments, the anticoagulant
included in the analyte sensor system may prevent coagulation
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.
[0217] In one embodiment, heparin is incorporated into the analyte
sensor system, for example by dipping or spraying. While not
wishing to be bound by theory, it is believed that heparin coated
on the catheter or sensor may prevent aggregation and clotting of
blood on the analyte sensor system, thereby preventing
thromboembolization (e.g., prevention of blood flow by the thrombus
or clot) or subsequent complications. In another embodiment, an
antimicrobial is coated on the catheter (inner or outer diameter)
or sensor.
[0218] In some embodiments, an antimicrobial agent may be
incorporated into the analyte sensor system. The antimicrobial
agents contemplated may include, but are not limited to,
antibiotics, antiseptics, disinfectants and synthetic moieties, and
combinations thereof, and other agents that are soluble in organic
solvents such as alcohols, ketones, ethers, aldehydes,
acetonitrile, acetic acid, methylene chloride and chloroform. The
amount of each antimicrobial agent used to impregnate the medical
device varies to some extent, but is at least of an effective
concentration to inhibit the growth of bacterial and fungal
organisms, such as staphylococci, gram-positive bacteria,
gram-negative bacilli and Candida.
[0219] In some embodiments, an antibiotic may be incorporated into
the analyte sensor system. Classes of antibiotics that can be used
include tetracyclines (e.g., minocycline), rifamycins (e.g.,
rifampin), macrolides (e.g., erythromycin), penicillins (e.g.,
nafeillin), cephalosporins (e.g., cefazolin), other beta-lactam
antibiotics (e.g., imipenem, aztreonam), aminoglycosides (e.g.,
gentamicin), chloramphenicol, sulfonamides (e.g.,
sulfamethoxazole), glycopeptides (e.g., vancomycin), quinolones
(e.g., ciprofloxacin), fusidic acid, trimethoprim, metronidazole,
clindamycin, mupirocin, polyenes (e.g., amphotericin B), azoles
(e.g., fluconazole), and beta-lactam inhibitors (e.g.,
sulbactam).
[0220] Examples of specific antibiotics that can be used include
minocycline, rifampin, erythromycin, nafcillin, cefazolin,
imipenem, aztreonam, gentamicin, sulfamethoxazole, vancomycin,
ciprofloxacin, trimethoprim, metronidazole, clindamycin,
teicoplanin, mupirocin, azithromycin, clarithromycin, ofloxacin,
lomefloxacin, norfloxacin, nalidixic acid, sparfloxacin,
pefloxacin, amifloxacin, enoxacin, fleroxacin, temafloxacin,
tosufloxacin, clinafloxacin, sulbactam, clavulanic acid,
amphotericin B, fluconazole, itraconazole, ketoconazole, and
nystatin.
[0221] In some embodiments, an antiseptic or disinfectant may be
incorporated into the analyte sensor system. Examples of
antiseptics and disinfectants are hexachlorophene, cationic
bisiguanides (e.g., chlorhexidine, cyclohexidine) iodine and
iodophores (e.g., povidoneiodine), para-chloro-meta-xylenol,
triclosan, furan medical preparations (e.g., nitrofurantoin,
nitrofurazone), methenamine, aldehydes (glutaraldehyde,
formaldehyde) and alcohols. Other examples of antiseptics and
disinfectants will readily suggest themselves to those of ordinary
skill in the art.
[0222] In some embodiments, an anti-barrier cell agent may be
incorporated into the analyte sensor system. Anti-barrier cell
agents may include compounds exhibiting effects on macrophages and
foreign body giant cells (FBGCs). It is believed that anti-barrier
cell agents prevent closure of the barrier to solute transport
presented by macrophages and FBGCs at the device-tissue interface
during FBC maturation. Anti-barrier cell agents may provide
anti-inflammatory or immunosuppressive mechanisms that affect the
wound healing process, for example, healing of the wound created by
the incision into which an implantable device is inserted.
Cyclosporine, which stimulates very high levels of
neovascularization around biomaterials, can be incorporated into a
bioprotective membrane of one embodiment (see U.S. Pat. No.
5,569,462 to Martinson et al.). Alternatively, Dexamethasone, which
abates the intensity of the FBC response at the tissue-device
interface, can be incorporated into a bioprotective membrane of one
embodiment. Alternatively, Rapamycin, which is a potent specific
inhibitor of some macrophage inflammatory functions, can be
incorporated into a bioprotective membrane of one embodiment.
[0223] In some embodiments, an, anti-inflammatory agent may be
incorporated into the analyte sensor system to reduce acute or
chronic inflammation adjacent to the implant or to decrease the
formation of a FBC capsule to reduce or prevent barrier cell layer
formation, for example. Suitable anti-inflammatory agents include
but are not limited to, for example, nonsteroidal anti-inflammatory
drugs (NSAIDs) such as acetometaphen, aminosalicylic acid, aspirin,
celecoxib, choline magnesium trisalicylate, diclofenac potassium,
diclofenac sodium, diflunisal, etodolac, fenoprofen, flurbiprofen,
ibuprofen, indomethacin, interleukin (IL)-10, IL-6 mutein,
anti-IL-6 iNOS inhibitors (for example, L-NAME or L-NMDA),
Interferon, ketoprofen, acetominophen, ketorolac, leflunomide,
melenamic acid, mycophenolic acid, mizoribine, nabumetone,
naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib,
salsalate, sulindac, and tolmetin; and corticosteroids such as
cortisone, hydrocortisone, methylprednisolone, prednisone,
prednisolone, betamethesone, beclomethasone dipropionate,
budesonide, dexamethasone sodium phosphate, flunisolide,
fluticasone propionate, paclitaxel, tacrolimus, tranilast,
triamcinolone acetonide, betamethasone, fluocinolone, fluocinonide,
betamethasone dipropionate, betamethasone valerate, desonide,
desoximetasone, fluocinolone, triamcinolone, triamcinolone
acetonide, clobetasol propionate, and dexamethasone.
[0224] In some embodiments, an immunosuppressive or
immunomodulatory agent may be incorporated into the analyte sensor
system in order to interfere directly with several key mechanisms
necessary for involvement of different cellular elements in the
inflammatory response. Suitable immunosuppressive and
immunomodulatory agents include, but are not limited to,
anti-proliferative, cell-cycle inhibitors, (for example,
paclitaxel, cytochalasin D, infiximab), taxol, actinomycin,
mitomycin, thospromote VEGF, estradiols, NO donors, QP-2,
tacrolimus, tranilast, actinomycin, everolimus, methothrexate,
mycophenolic acid, angiopeptin, vincristing, mitomycine, statins, C
MYC antisense, sirolimus (and analogs), RestenASE,
2-chloro-deoxyadenosine, PCNA Ribozyme, batimstat, prolyl
hydroxylase inhibitors, PPAR.gamma. ligands (for example
troglitazone, rosiglitazone, pioglitazone), halofuginone,
C-proteinase inhibitors, probucol, BCP671, EPC antibodies,
catchins, glycating agents, endothelin inhibitors (for example,
Ambrisentan, Tesosentan, Bosentan), Statins (for example,
Cerivasttin), E. coli heat-labile enterotoxin, and advanced
coatings.
[0225] In some embodiments, an anti-infective agent may be
incorporated into the analyte sensor system. In general,
anti-infective agents are substances capable of acting against
infection by inhibiting the spread of an infectious agent or by
killing the infectious agent outright, which can serve to reduce an
immuno-response without an inflammatory response at the implant
site, for example. Anti-infective agents include, but are not
limited to, anthelmintics (e.g., mebendazole), antibiotics (e.g.,
aminoclycosides, gentamicin, neomycin, tobramycin), antifungal
antibiotics (e.g., amphotericin b, fluconazole, griseofulvin,
itraconazole, ketoconazole, nystatin, micatin, tolnaftate),
cephalosporins (e.g., cefaclor, cefazolin, cefotaxime, ceftazidime,
ceftriaxone, cefuroxime, cephalexin), beta-lactam antibiotics
(e.g., cefotetan, meropenem), chloramphenicol, macrolides (e.g.,
azithromycin, clarithromycin, erythromycin), penicillins (e.g.,
penicillin G sodium salt, amoxicillin, ampicillin, dicloxacillin,
nafcillin, piperacillin, ticarcillin), tetracyclines (e.g.,
doxycycline, minocycline, tetracycline), bacitracin, clindamycin,
colistimethate sodium, polymyxin b sulfate, vancomycin, antivirals
(e.g., acyclovir, amantadine, didanosine, efavirenz, foscarnet,
ganciclovir, indinavir, lamivudine, nelfinavir, ritonavir,
saquinavir, silver, stavudine, valacyclovir, valganciclovir,
zidovudine), quinolones (e.g., ciprofloxacin, levofloxacin);
sulfonamides (e.g., sulfadiazine, sulfisoxazole), sulfones (e.g.,
dapsone), furazolidone, metronidazole, pentamidine, sulfanilamidum
crystallinum, gatifloxacin, and sulfamethoxazole/trimethoprim.
[0226] In some embodiments, a vascularization agent may be
incorporated into the analyte sensor system. Vascularization agents
generally may include substances with direct or indirect angiogenic
properties. In some cases, vascularization agents may additionally
affect formation of barrier cells in vivo. By indirect
angiogenesis, it is meant that the angiogenesis can be mediated
through inflammatory or immune stimulatory pathways. It is not
fully known how agents that induce local vascularization indirectly
inhibit barrier-cell formation; however, while not wishing to be
bound by theory, it is believed that some barrier-cell effects can
result indirectly from the effects of vascularization agents.
[0227] Vascularization agents may provide mechanisms that promote
neovascularization and accelerate wound healing around the membrane
or minimize periods of ischemia by increasing vascularization close
to the tissue-device interface. Sphingosine-1-Phosphate (S1P), a
phospholipid possessing potent angiogenic activity, may be
incorporated into the bioprotective membrane. Monobutyrin, a
vasodilator and angiogenic lipid product of adipocytes, may also be
incorporated into the bioprotective membrane. In another
embodiment, an anti-sense molecule (for example, thrombospondin-2
anti-sense), which may increase vascularization, is incorporated
into a bioprotective membrane.
[0228] Vascularization agents may provide mechanisms that promote
inflammation, which is believed to cause accelerated
neovascularization and wound healing in vivo. In one embodiment, a
xenogenic carrier, for example, bovine collagen, which by its
foreign nature invokes an immune response, stimulates
neovascularization, and is incorporated into a bioprotective
membrane of some embodiments. In another embodiment,
Lipopolysaccharide, an immunostimulant, may be incorporated into a
bioprotective membrane. In another embodiment, a protein, for
example, a bone morphogenetic protein (BMP), which is known to
modulate bone healing in tissue, may be incorporated into the
bioprotective membrane.
[0229] In some embodiments, an angiogenic agent may be incorporated
into the analyte sensor system. Angiogenic agents are substances
capable of stimulating neovascularization, which can accelerate and
sustain the development of a vascularized tissue bed at the
tissue-device interface, for example. Angiogenic agents include,
but are not limited to, Basic Fibroblast Growth Factor (bFGF),
(also known as Heparin Binding Growth Factor-II and Fibroblast
Growth Factor II), Acidic Fibroblast Growth Factor (aFGF), (also
known as Heparin Binding Growth Factor-I and Fibroblast Growth
Factor-I), Vascular Endothelial Growth Factor (VEGF), Platelet
Derived Endothelial Cell Growth Factor BB (PDEGF-BB),
Angiopoietin-1, Transforming Growth Factor Beta (TGF-.beta.),
Transforming Growth Factor Alpha (TGF-Alpha), Hepatocyte Growth
Factor, Tumor Necrosis Factor-Alpha (TNF.alpha.), Placental Growth
Factor (PLGF), Angiogenin, Interleukin-8 (IL-8), Hypoxia Inducible
Factor-I (HIF-1), Angiotensin-Converting Enzyme (ACE) Inhibitor
Quinaprilat, Angiotropin, Thrombospondin, Peptide KGHK, Low Oxygen
Tension, Lactic Acid, Insulin, Copper Sulphate, Estradiol,
prostaglandins, cox inhibitors, endothelial cell binding agents
(for example, decorin or vimentin), glenipin, hydrogen peroxide,
nicotine, and Growth Hormone.
[0230] In some embodiments, a pro-inflammatory agent may be
incorporated into the analyte sensor system. Pro-inflammatory
agents are generally substances capable of stimulating an immune
response in host tissue, which can accelerate or sustain formation
of a mature vascularized tissue bed. For example, pro-inflammatory
agents are generally irritants or other substances that induce
chronic inflammation and chronic granular response at the
wound-site. While not wishing to be bound by theory, it is believed
that formation of high tissue granulation induces blood vessels,
which supply an adequate or rich supply of analytes to the
device-tissue interface. Pro-inflammatory agents include, but are
not limited to, xenogenic carriers, Lipopolysaccharides, S. aureus
peptidoglycan, and proteins.
[0231] These bioactive agents can be used alone or in combination.
The bioactive agents can be dispersed throughout the material of
the sensor, for example, incorporated into at least a portion of
the membrane system, or incorporated into the device (e.g.,
housing) and adapted to diffuse through the membrane.
[0232] There are a variety of systems and methods by which a
bioactive agent may be incorporated into the sensor membrane. In
some embodiments, the bioactive agent may be 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 in some embodiments the
bioactive agent is incorporated into the membrane system, in other
embodiments the bioactive agent can be administered concurrently
with, prior to, or after insertion of the device in vivo, for
example, by oral administration, or locally, by subcutaneous
injection near the implantation site. A combination of bioactive
agent incorporated in the membrane system and bioactive agent
administration locally or systemically can be used in certain
embodiments.
[0233] In general, a bioactive agent can be incorporated into the
membrane system, or incorporated into the device and adapted to
diffuse therefrom, in order to modify the in vivo response of the
host to the membrane. In some embodiments, the bioactive agent may
be 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 or stages
of in vivo response (e.g., thrombus formation). In some alternative
embodiments however, the bioactive agent may be incorporated into
the device proximal to the membrane system, such that the bioactive
agent diffuses through the membrane system to the host circulatory
system.
[0234] 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,
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,
or any portion of the sensor system.
[0235] 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 from about 4, 8, 12, 16, or 20 hours to about 1, 2, 3, 4,
5, or 7 days).
[0236] 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 or encapsulated
within the polymer that forms the membrane system.
[0237] In yet another embodiment, microspheres are used to
encapsulate the bioactive agent. The microspheres can be formed of
biodegradable polymers, including 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 discloses some systems and
methods that can be used in conjunction with the disclosed
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.
[0238] 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 various 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.
[0239] 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.
[0240] 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. No. 4,506,680 and U.S. Pat. No. 5,282,844. In some
embodiments, the plug is disposed 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
[0241] Numerous variables can affect the pharmacokinetics of
bioactive agent release. The bioactive agents of the various
embodiments can be optimized for short- or long-term release. In
some embodiments, the bioactive agents of the various embodiments
are designed to aid or overcome factors associated with short-term
effects (e.g., acute inflammation or thrombosis) of sensor
insertion. In some embodiments, the bioactive agents of the various
embodiments are designed to aid or overcome factors associated with
long-term effects, for example, chronic inflammation or build-up of
fibrotic tissue or plaque material. In some embodiments, the
bioactive agents of the various embodiments combine short- and
long-term release to exploit the benefits of both.
[0242] 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.
[0243] Short-term release of the bioactive agent in the various
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
[0244] 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.
[0245] In some embodiments, in which the bioactive agent is
incorporated into the membrane system without a carrier matrix, the
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 can be sufficiently high
such that a biological effect (e.g., thrombosis prevention) is
observed. Above this threshold, the 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, 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, or 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, such as 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. %.
[0246] 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. The gel can contain from about 0.1
or less to about 50 wt. % or more of the bioactive agent(s), for
example 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), or 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.
[0247] Referring now to microencapsulated bioactive agents, the
release of the agents from these polymeric systems generally occurs
by two different mechanisms. The bioactive agent can be released by
diffusion through aqueous filled channels generated in the dosage
form by the dissolution of the agent or by voids created by the
removal of the polymer solvent or a pore forming agent during the
original micro-encapsulation. Alternatively, release can be
enhanced due to the degradation of the encapsulating polymer. With
time, the polymer erodes and generates increased porosity and
microstructure within the device. This creates additional pathways
for release of the bioactive agent.
[0248] 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.
EXAMPLES
Example 1
General Preparation of Layered Interference Domains
[0249] Layered interference domains were prepared as follows. Nine
poly(allylamine hydrochloride) (PAH) dip solutions were prepared by
dissolving PAH having a molecular weight of approximately
100,000-200,000 g/mol in water to produce an aqueous solution with
a concentration of approximately 50 mM of PAH. Each of the
resulting nine solutions was then titrated with acetic acid or
ammonium hydroxide to a pH of 10.0, 9.75, 9.5, 9.25, 9.0, 8.5, 8.0,
7.5, and 7.0, respectively.
[0250] Nine solutions for rinsing after PAH immersion were prepared
by titrating water with ammonium hydroxide until a pH of 10.0,
9.75, 9.5, 9.25, 9.0, 8.5, 8.0, 7.5, and 7.0, respectively, was
reached.
[0251] Five poly(acrylic acid) (PAA) dip solutions were prepared by
dissolving PAA having a molecular weight of approximately 100,000
g/mol in water to produce an aqueous solution with a concentration
of approximately 50 mM of PAA. Each of the resulting five solutions
was then titrated with acetic acid or ammonium hydroxide to a
specified pH of 2.5, 3.0, 4.0, 5.0, and 6.0, respectively.
[0252] Five solutions for rinsing after PAA immersion were prepared
by titrating water with acetic acid until a pH of 2.5, 3.0, 4.0,
5.0 and 6.0, respectively, was reached.
[0253] Various interference domains were prepared by sequentially
dipping a bare platinum wire into the PAH dip solution, followed by
dipping the wire into a rinse solution having a pH corresponding to
that of the PAH dip solution. This was followed by dipping the wire
into the PAA dip solution, then into a rinse solution having a pH
corresponding to that of the PAA dip solution. Interference domains
were prepared with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14
layers by sequentially dipping the wire into PAH dip/rinse
solutions followed by PAA dip/rinse solutions according to the
above procedure.
[0254] A nine-layered interference domain was prepared by: (1)
dipping a bare platinum wire into a PAH dip solution, then dipping
the wire into the corresponding rinse solution; (2) dipping the
wire into the PAA dip solution, then dipping the wire into the PAA
rinse solution; (3) dipping the wire into a PAH dip solution, then
dipping the wire into the corresponding rinse solution; (4) dipping
the wire into the PAA dip solution, then dipping the wire into the
corresponding rinse solution; (5) dipping the wire into a PAH dip
solution, then dipping the wire into the corresponding rinse
solution; (6) dipping the wire into the PAA dip solution, then
dipping the wire into the corresponding rinse solution; (7) dipping
the wire into a PAH dip solution, then dipping the wire into the
corresponding rinse solution; (8) dipping the wire into the PAA dip
solution, then dipping the wire into the corresponding rinse
solution; and (9) dipping the wire into a PAH dip solution, then
dipping the wire into the corresponding rinse solution. The
resulting nine-layered interference domain contained 5 layers of
PAH and 4 layers of PAA.
[0255] Other interference domains are prepared by dipping a wire
into alternating solutions of PAH, PDADMAC, PAA, PSS, and/or PVS.
An interference domain with a single layer is prepared, for
example, by dipping the wire into a PAH or PAA dip solution.
[0256] In alternative embodiments, interference domains can be
prepared whereby a polyanionic polymer is first deposited onto a
bare wire, for example, by dipping a bare wire into a polyanionic
solution (such as PAA), then into a rinse solution, then into a
polycationic solution (such as PAH), then into a rinse
solution.
Example 2
Preparation of PAH/PVS Interference Domains
[0257] Layered interference domains were prepared using
poly(allylamine hydrochloride) (PAH) and poly(vinyl sulfate) (PVS)
as follows. Dipping solutions of PAH and corresponding rinse
solutions were prepared according to Example 1.
[0258] Poly(vinyl sulfate) (PVS) dipping solutions and
corresponding rinse solutions were prepared in a manner
corresponding to the preparation of the PAA solutions described in
Example 1.
[0259] Various interference domains were prepared by sequentially
dipping a bare platinum wire into the PAH dip solution, followed by
the corresponding rinse solution, followed by the PVS dip solution,
and followed by the corresponding rinse solution. Interference
domains were prepared with 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
and 14 layers by sequentially dipping the wire into PAH dip/rinse
solutions followed by PVS dip/rinse solutions.
[0260] For example, a four-layered interference domain was prepared
by: (1) dipping a bare wire into a PAH dip solution, then dipping
the wire into the corresponding rinse solution; (2) dipping the
wire into the PVS dip solution, then dipping the wire into the
corresponding rinse solution; (3) dipping the wire into a PAH dip
solution, then dipping the wire into the corresponding rinse
solution; and (4) dipping the wire into the PVS dip solution, then
dipping the wire into the corresponding rinse solution. The
resulting four-layered interference domain contained 2 layers of
PAH and 2 layers of PVS.
[0261] An interference domain with a single layer of PAH was
prepared by dipping the wire into a PAH dip solution.
Example 3
Effect of Different Numbers of PAH/PVS Layers
[0262] The number of PAH and PVS layers in interference domains was
varied to determine the effect of the number of layers on the
permeability of the resulting interference domain to
H.sub.2O.sub.2, acetaminophen, ascorbic acid, and uric acid.
Sensors were prepared comprising platinum electrodes coated with
interference domains prepared according to the procedure described
in Example 2. Specifically, an interference domain containing a
single layer of PAH was prepared. Also, interference domains
containing 2, 3, and 4 layers of alternating PAH and PVS layers
were prepared. An enzyme domain was added according to methods
known in the art. The resulting sensors were sequentially placed
into solutions that contained either H.sub.2O.sub.2, acetaminophen,
ascorbic acid, or uric acid. The average current response (pA) for
each solution was measured. The sensitivity of the current response
versus the concentration of H.sub.2O.sub.2 was determined. The
selectivity of the interference domain with respect to
H.sub.2O.sub.2 was determined for acetaminophen, ascorbic acid, and
uric acid. A sensor containing an enzyme domain, without an
interference domain, was tested as a control. The results are shown
in Table 1 and FIGS. 5A and 5B. The data demonstrates that the
interference domain possessed high sensitivity to H.sub.2O.sub.2
for interference domains having from 1 to 4 layers, with a slight
drop-off observed at 3 layers, and the ability to substantially
block acetaminophen (2 to 4 layers) and uric acid (1, 2, or 4
layers).
TABLE-US-00003 TABLE 1 Sensitivity to H.sub.2O.sub.2 (pA response/
Selectivity- Selectivity- Selectivity- Sensor .mu.M H.sub.2O.sub.2)
acetaminophen ascorbic acid uric acid Interference 2336 0.59 0.55
0.27 Domain: 1 layer of PAH Interference 2438 0.30 0.53 0.21
Domain: 2 layers PAH/PVS Interference 1844 0.52 0.60 0.30 Domain: 3
layers PAH/PVS Interference 1719 0.27 0.56 0.17 Domain: 4 layers
PAH/PVS No interference 2281 0.64 0.58 0.35 domain Note:
Selectivity is calculated by dividing the sensitivity to the
interferent (e.g., acetaminophen, ascorbic acid, or uric acid) by
the H.sub.2O.sub.2 sensitivity.
Example 4
Effect of pH on H.sub.2O.sub.2 and Acetaminophen Permeability
[0263] The pH of PAH and PAA dip solutions was varied to determine
the effect of pH on the resulting interference domains'
permeability to H.sub.2O.sub.2 and acetaminophen. Interference
domains were prepared according to the procedure described in
Example 1, and deposited upon a platinum wire electrode. The pH of
PAH and PAA dipping solutions used to prepare the interference
domains, and the number of layers of PAH and PAA in each
interference domain are shown in Tables 2 and 3. Each of the
interference domains shown in Table 1 were sequentially placed into
the following seven solutions: (1) PBS buffer at a pH of 7.3 at
37.degree. C.; (2) 2 .mu.M aqueous H.sub.2O.sub.2; (3) 4 .mu.M
aqueous H.sub.2O.sub.2; (4) 6 .mu.M aqueous H.sub.2O.sub.2; (5) 132
.mu.M aqueous acetaminophen; (6) 264 .mu.M aqueous acetaminophen;
and (7) 396 .mu.M aqueous acetaminophen. The average current
response (pA) of each of the seven solutions was measured. The
sensitivity of the current response versus the concentration of
H.sub.2O.sub.2 was determined for solutions (2)-(4). The
sensitivity of the current response versus the concentration of
acetaminophen was determined for solutions (5)-(7). The results are
shown in Tables 2 and 3, and in FIGS. 6A and 6B. The data show that
PAA solutions of low pH (i.e., less than 3) produce interference
layers with diminished response to acetaminophen. The data also
show that PAH solutions of high pH (i.e., greater than 8) produce
interference layers with diminished response to acetaminophen.
TABLE-US-00004 TABLE 2 Sensitivity Sensitivity to pH of PAH Number
pH of PAA Number to H.sub.2O.sub.2 (pA acetaminophen dipping of PAH
dipping of PAA response/ (pA response/.mu.M Selectivity- solution
layers solution layers .mu.M H.sub.2O.sub.2) acetaminophen)
acetaminophen 10.0 5 2.5 4 961 7 0.007 10.0 5 3.0 4 768 5 0.007
10.0 5 4.0 4 1346 23 0.017 10.0 5 5.0 4 1609 28 0.017 10.0 5 6.0 4
1664 21 0.013
TABLE-US-00005 TABLE 3 Sensitivity Sensitivity to pH of PAH Number
pH of PAA Number to H.sub.2O.sub.2 (pA acetaminophen dipping of PAH
dipping of PAA response/ (pA response/.mu.M Selectivity- solution
layers solution layers .mu.M H.sub.2O.sub.2) acetaminophen)
acetaminophen 10.0 5 3.0 4 1199 10 0.0083 9.75 5 3.0 4 1253 11
0.0088 9.5 5 3.0 4 1276 10 0.0078 9.25 5 3.0 4 1292 11 0.0085 9.0 5
3.0 4 1267 12 0.0095 8.5 5 3.0 4 1438 16 0.011 8.0 5 3.0 4 1550 18
0.012 7.5 5 3.0 4 2071 122 0.0589 7.0 5 3.0 4 2222 122 0.0549
Example 5
pH Effect on Acetaminophen Performance
[0264] The effect of pH of PAH and PAA dipping solutions on
interference domain sensitivity to acetaminophen was determined.
Interference domains were prepared according to the procedure
described in Example 1 and deposited on a platinum wire.
Specifically, interference domains containing 9 total alternating
layers of PAH and PAA were prepared. The results are shown in
Tables 4 and 5, and in FIGS. 7A and 7B. The results demonstrate a
substantial reduction in sensitivity to acetaminophen when a basic
pH PAH solution having a pH above 9 is combined with an acidic PAA
solution having a pH below 3.
TABLE-US-00006 TABLE 4 pH of pH of Sensitivity to PAH Number PAA
Number acetaminophen dipping of PAH dipping of PAA (pA
response/.mu.M solution layers solution layers acetaminophen) 9.5 5
4.0 4 41 9.5 5 3.5 4 20 9.5 5 3.25 4 24 9.5 5 3.0 4 22 9.5 5 2.75 4
14 9.5 5 2.5 4 8 9.5 5 2.25 4 11
TABLE-US-00007 TABLE 5 pH of pH of Sensitivity to PAH Number PAA
Number acetaminophen dipping of PAH dipping of PAA (pA
response/.mu.M solution layers solution layers acetaminophen) 10.0
5 3.0 4 30 9.75 5 3.0 4 20 9.5 5 3.0 4 22 9.5 5 3.0 4 22 9.25 5 3.0
4 25 9.0 5 3.0 4 53
Example 6
Effect of Different Number of Layers
[0265] The number of PAH and PAA layers in interference domains was
varied to determine the effect of the number of layers on the
resulting interference domain's permeability to H.sub.2O.sub.2 and
acetaminophen. Various interference domains were prepared according
to the procedure described in Example 1 and deposited on a platinum
wire. Specifically, interference domains containing 3, 5, 7, and 9
layers of alternating PAH and PAA layers were prepared. Then an
enzyme domain was added according to methods known in the art. Each
of the sensors were sequentially placed into the following eight
solutions: (1) PBS buffer at a pH of 7.3 at 37.degree. C.; (2) 1
.mu.M aqueous H.sub.2O.sub.2; (3) 2 .mu.M aqueous H.sub.2O.sub.2;
(4) 3 .mu.M aqueous H.sub.2O.sub.2; (5) PBS buffer at a pH of 7.3
at 37.degree. C.; (6) 10 .mu.M aqueous acetaminophen; (7) 50 .mu.M
aqueous acetaminophen; and (8) 100 .mu.M aqueous acetaminophen. The
average current response (pA) for each of the eight solutions was
measured. The sensitivity of the current response versus the
concentration of H.sub.2O.sub.2 was determined for solutions
(2)-(4). The sensitivity of the current response versus the
concentration of acetaminophen was determined for solutions
(6)-(8). A sensor containing a polyurethane electrode domain and an
enzyme domain was tested as a control. The results are shown in
Table 6, and in FIGS. 8A and 8B. An increase in number of layers
resulted in an incremental but acceptably low decrease in
sensitivity to H.sub.2O.sub.2, with a disproportionate reduction in
sensitivity to acetaminophen. A particularly dramatic decrease in
sensitivity to acetaminophen was observed in going from three
layers to five layers.
TABLE-US-00008 TABLE 6 Selectivity- Sensitivity to Sensitivity to
acetaminophen H.sub.2O.sub.2 acetaminophen (sensitivity (pA
response/ (pA response/.mu.M acetaminophen/ sensor .mu.M
H.sub.2O.sub.2) acetaminophen) sensitivity H.sub.2O.sub.2)
Interference 2126 101 0.047 Domain: 3 layers PAH/PAA Interference
1857 24 0.013 Domain: 5 layers PAH/PAA Interference 1482 12 0.008
Domain: 7 layers PAH/PAA Interference 1280 8 0.006 Domain: 9 layers
PAH/PAA Interference 1082 5 0.005 Domain: 21 layers PAH/PAA
Interference 1137 5 0.004 Domain: 23 layers PAH/PAA Interference
965 4 0.004 Domain: 25 layers PAH/PAA Interference 1027 5 0.005
Domain: 27 layers PAH/PAA Interference 953 4 0.004 Domain: 29
layers PAH/PAA Interference 844 4 0.005 Domain: 31 layers PAH/PAA
Control 2593 1587 0.614
Example 7
[0266] The effect of first depositing a cationic layer versus first
depositing an anionic layer on sensitivity and selectivity of the
resulting interference domain was determined. Interference domains
were prepared according to the procedure described in Example 1 and
deposited on platinum wire.
[0267] Specifically, a first interference domain containing 9 total
alternating layers of PAH and PAA was prepared. The first layer
deposited on the platinum wire for first interference domain was
the cationic polymer PAH. Therefore, the first interference domain
contained the following layers: Layer 1=PAH, Layer 2=PAA, Layer
3=PAH, Layer 4=PAA, Layer 5=PAH, Layer 6=PAA, Layer 7=PAH, Layer
8=PAA, Layer 9=PAH.
[0268] A second interference domain containing 9 total alternating
layers of PAA and PAH was prepared. The first layer deposited on
the platinum wire for the second interference domain was the
anionic polymer PAA. Therefore, the second interference domain
contained the following layers: Layer 1=PAA, Layer 2=PAH, Layer
3=PAA, Layer 4=PAH, Layer 5=PAA, Layer 6=PAH, Layer 7=PAA, Layer
8=PAH, Layer 9=PAA.
[0269] The sensitivity to H.sub.2O.sub.2, sensitivity to
acetaminophen, and selectivity were determined for both
interference domains with and without an added enzyme domain. The
results are shown in Table 7.
TABLE-US-00009 TABLE 7 Selectivity- Sensitivity to Sensitivity to
acetaminophen H.sub.2O.sub.2 acetaminophen (sensitivity (pA
response/ (pA response/.mu.M acetaminophen/ sensor .mu.M
H.sub.2O.sub.2) acetaminophen) sensitivity H.sub.2O.sub.2) First
Interference 2,875 20 0.007 Domain (PAH layer first) First
Interference 2,374 27 0.012 Domain (PAH layer first) + Enzyme
Domain Second 4,469 34 0.080 Interference Domain (PAA layer first)
Second 1,733 52 0.030 Interference Domain (PAA layer first) +
Enzyme Domain
Example 8
Preparation of PAH/PSS Interference Domains
[0270] Layered interference domains are prepared using
poly(allylamine hydrochloride) (PAH) and poly(styrene sulfate)
(PSS) as follows. PAH dipping and rinse solutions are prepared
according to Example 1.
[0271] Poly(styrene sulfate) (PSS) dipping and rinse solutions are
prepared in a manner to the preparation of the PAA solutions
described in Example 1.
[0272] Interference domains are prepared by sequentially dipping a
bare wire, e.g., a platinum wire, into the PAH dip solution,
followed by the corresponding rinse solution, followed by the PSS
dip solution, and followed by the corresponding rinse solution.
Interference domains are prepared with 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, and 14 layers by sequentially dipping the wire into PAH
dip/rinse solutions, followed by PSS dip/rinse solutions.
[0273] For example, a seven-layered interference domain can be
prepared by: (1) dipping a bare wire into a PAH dip solution, then
dipping the wire into the corresponding rinse solution; (2) dipping
the wire into the PSS dip solution, then dipping the wire into the
corresponding rinse solution; (3) dipping the wire into a PAH dip
solution, then dipping the wire into the corresponding rinse
solution; (4) dipping the wire into the PSS dip solution, then
dipping the wire into the corresponding rinse solution; (5) dipping
the wire into a PAH dip solution, then dipping the wire into the
corresponding rinse solution; (6) dipping the wire into the PSS dip
solution, then dipping the wire into the corresponding rinse
solution; and (7) dipping the wire into a PAH dip solution, then
dipping the wire into the corresponding rinse solution.
[0274] The resulting seven-layered interference domain contains 4
layers of PAH and 3 layers of PSS.
Example 9
Preparation of PDADMAC/PAA Interference Domains
[0275] Layered interference domains are prepared using
poly(diallyldimethylammonium chloride) (PDADMAC) and poly(acrylic
acid) (PAA) as follows. PDADMAC dipping and rinse solutions are
prepared in a similar manner as the PAH solutions described in
Example 1.
[0276] PAA dipping and rinse solutions are prepared as described in
Example 1.
[0277] Various interference domains are prepared by sequentially
dipping a bare wire, e.g., a platinum wire, into the PDADMAC dip
solution, followed by the corresponding rinse solution, followed by
the PAA dip solution, and followed by the corresponding rinse
solution. Interference domains are prepared with 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, 12, 13, and 14 layers by sequentially dipping the
wire into PDADMAC dip/rinse solutions followed by PAA dip/rinse
solutions.
[0278] For example, an six-layered interference domain can be
prepared by: (1) dipping a bare wire into a PDADMAC dip solution,
then dipping the wire into the corresponding rinse solution; (2)
dipping the wire into the PAA dip solution, then dipping the wire
into the corresponding rinse solution; (3) dipping the wire into a
PDADMAC dip solution, then dipping the wire into the corresponding
rinse solution; (4) dipping the wire into the PAA dip solution,
then dipping the wire into the corresponding rinse solution; (5)
dipping the wire into a PDADMAC dip solution, then dipping the wire
into the corresponding rinse solution; and (6) dipping the wire
into the PAA dip solution, then dipping the wire into the
corresponding rinse solution.
[0279] The resulting six-layered interference domain contains 3
layers of PDADMAC and 3 layers of PSS.
Example 10
Preparation of PDADMAC/PSS Interference Domains
[0280] Layered interference domains are prepared using
poly(diallyldimethylammonium chloride) (PDADMAC) and poly(styrene
sulfonate) (PSS) as follows. PDADMAC dipping and rinse solutions
are prepared in a similar manner as the PAH solutions described in
Example 1.
[0281] PSS dipping and rinse solutions are prepared in a similar
manner as the PAA solutions described in Example 1.
[0282] Interference domains are prepared by sequentially dipping a
bare wire, e.g., a platinum wire, into the PDADMAC dip solution,
followed by the corresponding rinse solution, followed by the PSS
dip solution, and followed by the corresponding rinse solution.
Interference domains are prepared with 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, and 14 layers by sequentially dipping the wire into
PDADMAC dip/rinse solutions followed by PSS dip/rinse
solutions.
[0283] For example, an five-layered interference domain can be
prepared by: (1) dipping a bare wire into a PDADMAC dip solution,
then dipping the wire into the corresponding rinse solution; (2)
dipping the wire into the PSS dip solution, then dipping the wire
into the corresponding rinse solution; (3) dipping the wire into a
PDADMAC dip solution, then dipping the wire into the corresponding
rinse solution; (4) dipping the wire into the PSS dip solution,
then dipping the wire into the corresponding rinse solution; and
(5) dipping the wire into a PDADMAC dip solution, then dipping the
wire into the corresponding rinse solution.
[0284] The resulting five-layered interference domain contains 3
layers of PDADMAC and 2 layers of PSS.
Example 11
Preparation of Poly(Acetylene) Interference Domains
[0285] Layered interference domains are prepared using
poly(acetylene) as follows. A dipping solution of poly(acetylene)
is prepared by dissolving poly(acetylene) in a suitable solvent,
such as dichloromethane or as a colloidal suspension.
[0286] Interference domains are prepared by sequentially dipping a
bare wire, e.g., a platinum wire, into the poly(acetylene) dip
solution, followed by a time period where the wire is permitted to
dry, followed by dipping the wire into the poly(acetylene)
solution, and followed by a time period where the wire is permitted
to dry. Interference domains are prepared with 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, and 14 layers by sequentially dipping the wire
into the poly(acetylene) dip solution.
[0287] For example, a four-layered interference domain can be
prepared by: (1) dipping a bare wire into the poly(acetylene) dip
solution, then waiting for the wire to dry; (2) dipping the wire
into the poly(acetylene) dip solution, then waiting for the wire to
dry; (3) dipping the wire into the poly(acetylene) dip solution,
then waiting for the wire to dry; and (4) dipping the into the
poly(acetylene) dip solution, then waiting for the wire to dry.
Example 12
Preparation of Poly(p-phenylene) Interference Domains
[0288] Layered interference domains are prepared using
poly(p-phenylene) as follows. A dipping solution of
poly(p-phenylene) is prepared by dissolving poly(p-phenylene) in a
suitable solvent, such as dichloromethane.
[0289] Various interference domains are prepared by sequentially
dipping a bare wire, e.g., a platinum wire, into the
poly(p-phenylene) dip solution, followed by a time period where the
wire is permitted to dry, followed by dipping the wire into the
poly(p-phenylene) solution, and followed by a time period where the
wire is permitted to dry. Interference domains are prepared with 2,
3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14 layers by sequentially
dipping the wire into the poly(p-phenylene) dip solution.
[0290] For example, an three-layered interference domain can be
prepared by: (1) dipping a bare wire into the poly(p-phenylene) dip
solution, then waiting for the wire to dry; (2) dipping the wire
into the poly(p-phenylene) dip solution, then waiting for the wire
to dry; and (3) dipping the wire into the poly(p-phenylene) dip
solution, then waiting for the wire to dry.
[0291] Terms and phrases used in this document, and variations
thereof, unless otherwise expressly stated, should be construed as
open ended as opposed to limiting. As examples of the foregoing,
the term `including` should be read to mean `including, without
limitation` or the like; 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; the term `example` is used to
provide exemplary instances of the item in discussion, not an
exhaustive or limiting list thereof; and adjectives such as
`known`, `normal`, `standard`, and terms of similar meaning should
not be construed as limiting the item described to a given time
period or to an item available as of a given time, but instead
should be read to encompass known, normal, or standard technologies
that may be available or known now or at any time in the future.
Likewise, a group of items linked with the conjunction `and` should
not be read as requiring that each and every one of those items be
present in the grouping, but rather should be read as `and/or`
unless expressly stated otherwise. Similarly, a group of items
linked with the conjunction `or` should not be read as requiring
mutual exclusivity among that group, but rather should be read as
`and/or` unless expressly stated otherwise. In addition, as used in
this application, the articles `a` and `an` should be construed as
referring to one or more than one (i.e., to at least one) of the
grammatical objects of the article. By way of example, `an element`
means one element or more than one element.
[0292] The presence in some instances of broadening words and
phrases such as `one or more`, `at least`, `but not limited to`, or
other like phrases shall not be read to mean that the narrower case
is intended or required in instances where such broadening phrases
may be absent.
[0293] 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.
[0294] Furthermore, although the foregoing has been described in
some detail by way of illustrations and examples for purposes of
clarity and understanding, it is apparent to those skilled in the
art that certain changes and modifications may be practiced.
Therefore, the description and examples should not be construed as
limiting the scope of the invention to the specific embodiments and
examples described herein, but rather to also cover all
modification and alternatives coming with the true scope and spirit
of the invention.
* * * * *