U.S. patent application number 12/829340 was filed with the patent office on 2011-02-03 for continuous analyte sensors and methods of making same.
This patent application is currently assigned to DexCom, Inc.. Invention is credited to Robert Boock, Jeff Jackson, Jason Mitchell, Huashi Zhang.
Application Number | 20110027458 12/829340 |
Document ID | / |
Family ID | 43411768 |
Filed Date | 2011-02-03 |
United States Patent
Application |
20110027458 |
Kind Code |
A1 |
Boock; Robert ; et
al. |
February 3, 2011 |
CONTINUOUS ANALYTE SENSORS AND METHODS OF MAKING SAME
Abstract
Described here are embodiments of processes and systems for the
continuous manufacturing of implantable continuous analyte sensors.
In some embodiments, a method is provided for sequentially
advancing an elongated conductive body through a plurality of
stations, each configured to treat the elongated conductive body.
In some of these embodiments, one or more of the stations is
configured to coat the elongated conductive body using a meniscus
coating process, whereby a solution formed of a polymer and a
solvent is prepared, the solution is continuously circulated to
provide a meniscus on a top portion of a vessel holding the
solution, and the elongated conductive body is advanced through the
meniscus. The method may also comprise the step of removing excess
coating material from the elongated conductive body by advancing
the elongated conductive body through a die orifice. For example, a
provided elongated conductive body 510 is advanced through a
pre-coating treatment station 520, through a coating station 530,
through a thickness control station 540, through a drying or curing
station 550, through a thickness measurement station 560, and
through a post-coating treatment station 570.
Inventors: |
Boock; Robert; (Carlsbad,
CA) ; Jackson; Jeff; (Poway, CA) ; Zhang;
Huashi; (San Diego, CA) ; Mitchell; Jason;
(San Diego, CA) |
Correspondence
Address: |
KNOBBE, MARTENS, OLSEN & BEAR, LLP
2040 MAIN STREET, FOURTEENTH FLOOR
IRVINE
CA
92614
US
|
Assignee: |
DexCom, Inc.
San Diego
CA
|
Family ID: |
43411768 |
Appl. No.: |
12/829340 |
Filed: |
July 1, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61222716 |
Jul 2, 2009 |
|
|
|
61222815 |
Jul 2, 2009 |
|
|
|
61222751 |
Jul 2, 2009 |
|
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Current U.S.
Class: |
427/9 |
Current CPC
Class: |
A61B 2562/125 20130101;
A61B 5/14546 20130101; A61B 5/14532 20130101; A61B 5/14517
20130101; A61B 5/1473 20130101; A61B 2562/0209 20130101; A61B
2562/043 20130101; A61B 5/14865 20130101; B05C 3/10 20130101; A61B
5/1451 20130101; A61B 5/14503 20130101; A61B 2560/0223
20130101 |
Class at
Publication: |
427/9 |
International
Class: |
B05D 5/12 20060101
B05D005/12; B05D 1/38 20060101 B05D001/38; B05D 3/02 20060101
B05D003/02 |
Claims
1. A method for manufacturing a continuous analyte sensor, the
method comprising: applying a conductive material to an elongated
conductive body by advancing the elongated conductive body through
a liquid comprising the conductive material; drying or curing the
applied liquid to form a coating of the conductive material on the
elongated conductive body, the coating comprising a portion of the
continuous analyte sensor; determining whether a thickness of the
coating is within a predetermined range; and, if the thickness is
below the predetermined range, repeating steps of applying a
conductive material and drying or curing the applied liquid until
the thickness of the coating is determined to be within the
predetermined range, whereby a continuous analyte sensor configured
for in vivo use is obtained.
2. The method of claim 1, further comprising removing a fraction of
the conductive material applied to the elongated conductive
body.
3. The method of claim 1, wherein removing is performed by
advancing the elongated conductive body through a die.
4. The method of claim 1, wherein the conductive material is
Ag/AgCl.
5. The method of claim 1, wherein the predetermined range of the
thickness of the coating is from about 1 micron to about 20
microns.
6. The method of claim 1, wherein the conductive material is
platinum.
7. The method of claim 1, wherein the predetermined range is from
about 1 micron to about 10 microns.
8. The method of claim 1, further comprising applying an adhesion
promoter to the elongated conductive body before applying the
conductive material.
9. The method of claim 1, further comprising etching a portion of
the coating.
10. The method of claim 1, further comprising cutting the elongated
conductive body into a plurality of sections.
11. The method claim 1, wherein each section is associated with an
individual continuous analyte sensor.
12. The method of claim 1, wherein the conductive material is
Ag/AgCl.
13. The method of claim 1, wherein the conductive material has a
particle size associated with a maximum particle dimension that is
less than about 100 microns.
14. The method of claim 1, wherein the elongated conductive body is
a wire with a circular cross-sectional shape or a substantially
circular cross-sectional shape.
15. The method of claim 1, wherein the elongated conductive body
comprises an outer surface comprising an insulating material
selected from the group consisting of polyurethane, polyethylene,
and polyimide.
16. The method of claim 1, wherein applying a conductive material
is performed by a reel-to-reel system.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 35
U.S.C. .sctn.119(e) to U.S. Provisional Application No. 61/222,716
filed on Jul. 2, 2009, U.S. Provisional Application No. 61/222,815
filed on Jul. 2, 2009, and U.S. Provisional Application No.
61/222,751 filed on Jul. 2, 2009, the disclosures of which are
hereby expressly incorporated by reference in their entireties and
are hereby expressly made a portion of this application.
FIELD OF THE INVENTION
[0002] The embodiments described herein relate generally to
continuous analyte sensors and systems and methods for making these
sensors.
BACKGROUND OF THE INVENTION
[0003] Diabetes mellitus is a chronic disease, which occurs when
the pancreas does not produce enough insulin (Type I), or when the
body cannot effectively use the insulin it produces (Type II). This
condition typically leads to an increased concentration of glucose
in the blood (hyperglycemia), which can cause an array of
physiological derangements (e.g., kidney failure, skin ulcers, or
bleeding into the vitreous of the eye) associated with the
deterioration of small blood vessels. Sometimes, a hypoglycemic
reaction (low blood sugar) is induced by an inadvertent overdose of
insulin, or after a normal dose of insulin or glucose-lowering
agent accompanied by extraordinary exercise or insufficient food
intake.
[0004] A variety of implantable continuous electrochemical analyte
sensors have been developed for continuously measuring blood
glucose concentrations. Typically, these types of sensors have been
made by batch processes, which may not be suitable for large-scale,
low-cost manufacturing, and which often result in batch-to-batch
variations, thereby resulting in property variations among the
sensors produced.
SUMMARY OF THE INVENTION
[0005] Accordingly, there is a need for a process and system that
will reduce production costs through labor reduction and minimize
variations among the sensors produced, by providing automated,
continuous manufacturing of continuous analyte sensors.
[0006] In a first aspect, a method is provided for manufacturing a
continuous analyte sensor, the method comprising applying an
insulating material to an elongated conductive body comprising a
conductive surface by advancing the elongated conductive body
through a meniscus comprising the insulating material; and drying
or curing the applied insulating material to form a coating of the
insulating material on the elongated conductive body, the coating
comprising a portion of the continuous analyte sensor, whereby a
continuous analyte sensor configured for in vivo use is
obtained.
[0007] In an embodiment of the first aspect, the method further
comprises continuously circulating a liquid comprising the
insulating material in a vessel, whereby the meniscus is provided
at a wall of the vessel.
[0008] In an embodiment of the first aspect, the method further
comprises removing a fraction of the insulating material applied to
the elongated conductive body.
[0009] In an embodiment of the first aspect, removing is performed
by advancing the elongated conductive body through a die.
[0010] In an embodiment of the first aspect, the method further
comprises determining whether a thickness of the coating is within
a predetermined range; and repeating applying the insulating
material to the elongated conductive body if the thickness of the
coating is outside of the predetermined range.
[0011] In an embodiment of the first aspect, the predetermined
range of the thickness of the coating is from about 5 microns to
about 50 microns.
[0012] In an embodiment of the first aspect, the method further
comprises applying an adhesion promoter to the elongated conductive
body before applying the insulating material.
[0013] In an embodiment of the first aspect, the method further
comprises etching a portion of the coating.
[0014] In an embodiment of the first aspect, the method further
comprises cutting the elongated conductive body into a plurality of
sections.
[0015] In an embodiment of the first aspect, each section is
associated with an individual continuous analyte sensor.
[0016] In an embodiment of the first aspect, the insulating
material is selected from the group consisting of polyurethane,
polyethylene, and polyimide.
[0017] In an embodiment of the first aspect, the elongated
conductive body is a wire with a circular cross-sectional shape or
a substantially circular cross-sectional shape.
[0018] In an embodiment of the first aspect, the conductive surface
of the elongated conductive body comprises platinum.
[0019] In an embodiment of the first aspect, the conductive surface
of the elongated conductive body comprises at least one conductive
material selected from the group consisting of platinum-iridium,
gold, palladium, iridium, graphite, carbon, conductive polymers,
and combinations thereof.
[0020] In an embodiment of the first aspect, advancing the
elongated conductive body through the meniscus is performed by a
reel-to-reel system.
[0021] In a second aspect, a method is provided for manufacturing a
continuous analyte sensor, the method comprising applying a
conductive material to an elongated conductive body by advancing
the elongated conductive body through a liquid comprising the
conductive material; drying or curing the applied liquid to form a
coating of the conductive material on the elongated conductive
body, the coating comprising a portion of the continuous analyte
sensor; determining whether a thickness of the coating is within a
predetermined range; and, if the thickness is below the
predetermined range, repeating steps of applying a conductive
material and drying or curing the applied liquid until the
thickness of the coating is determined to be within the
predetermined range, whereby a continuous analyte sensor configured
for in vivo use is obtained.
[0022] In an embodiment of the second aspect, the method further
comprises removing a fraction of the conductive material applied to
the elongated conductive body.
[0023] In an embodiment of the second aspect, removing is performed
by advancing the elongated conductive body through a die.
[0024] In an embodiment of the second aspect, the conductive
material is Ag/AgCl.
[0025] In an embodiment of the second aspect, the predetermined
range of the thickness of the coating is from about 1 micron to
about 20 microns.
[0026] In an embodiment of the second aspect, the conductive
material is platinum.
[0027] In an embodiment of the second aspect, the predetermined
range is from about 1 micron to about 10 microns.
[0028] In an embodiment of the second aspect, the method further
comprises applying an adhesion promoter to the elongated conductive
body before applying the conductive material.
[0029] In an embodiment of the second aspect, the method further
comprises etching a portion of the coating.
[0030] In an embodiment of the second aspect, the method further
comprises cutting the elongated conductive body into a plurality of
sections.
[0031] In an embodiment of the second aspect, each section is
associated with an individual continuous analyte sensor.
[0032] In an embodiment of the second aspect, the conductive
material is Ag/AgCl.
[0033] In an embodiment of the second aspect, the conductive
material has a particle size associated with a maximum particle
dimension that is less than about 100 microns.
[0034] In an embodiment of the second aspect, the elongated
conductive body is a wire with a circular cross-sectional shape or
a substantially circular cross-sectional shape.
[0035] In an embodiment of the second aspect, the elongated
conductive body comprises an outer surface comprising an insulating
material selected from the group consisting of polyurethane,
polyethylene, and polyimide.
[0036] In an embodiment of the second aspect, applying a conductive
material is performed by a reel-to-reel system.
[0037] In a third aspect, a system is provided for manufacturing a
continuous analyte sensor, the system comprising a coating vessel
configured to hold a coating material in liquid form; a
reel-to-reel system configured to advance an elongated conductive
body through the coating material, whereby the coating material is
applied to the elongated conductive body; a thickness measurement
sensor configured to measure a dimension indicative of a thickness
of a coating formed from the coating material applied to the
elongated conductive body; an etching system configured to remove a
portion of the coating material applied to the elongated conductive
body; and a cutter configured to cut the elongated conductive body
into a plurality of sections, wherein each section is associated
with an individual continuous analyte sensor.
[0038] In an embodiment of the third aspect, the system further
comprises a die configured to remove a portion of the coating
material applied to the elongated conductive body.
[0039] In an embodiment of the third aspect, the elongated
conductive body is a wire with a circular cross-sectional shape or
a substantially circular cross-sectional shape.
[0040] In an embodiment of the third aspect, the coating material
comprises an insulating material selected from the group consisting
of polyurethane, polyethylene, and polyimide.
[0041] In an embodiment of the third aspect, the coating material
comprises a conductive material selected from the group consisting
of platinum, silver/silver chloride, platinum-iridium, gold,
palladium, iridium, graphite, carbon, conductive polymers, and
alloys and combinations thereof.
[0042] In an embodiment of the third aspect, the system further
comprises a pump and conduit system configured to circulate the
coating material in liquid form in the coating vessel to provide a
meniscus at a wall of the coating vessel.
[0043] In an embodiment of the third aspect, coating material is a
component of a solution, wherein the solution is controlled to have
a predetermined viscosity.
[0044] In an embodiment of the third aspect, the viscosity is
controlled by selecting a concentration of the coating material in
the solution or by selecting a solution temperature.
BRIEF DESCRIPTION OF THE DRAWINGS
[0045] FIG. 1A is a schematic diagram of one embodiment of an
automated, continuous system for manufacturing continuous analyte
sensors; FIG. 1B is a schematic diagram of another embodiment of an
automated, continuous system for manufacturing continuous analyte
sensors; FIG. 1C is a schematic diagram of yet another embodiment
of an automated, continuous system for manufacturing continuous
analyte sensors; FIG. 1D is a schematic diagram of yet another
embodiment of an automated, continuous system for manufacturing
continuous analyte sensors; FIG. 1E is a schematic diagram of yet
another embodiment of an automated, continuous system for
manufacturing continuous analyte sensors.
[0046] FIG. 2A is a side view of one embodiment of a transport
mechanism; FIG. 2B is a front view of the embodiment illustrated in
FIG. 2A.
[0047] FIG. 3A is a schematic diagram of one embodiment of a
coating station; FIG. 3B is a schematic diagram providing a
detailed view of the interface between the elongated conductive
body and the meniscus, of the embodiment illustrated in FIG. 3A;
FIG. 3C is a schematic diagram of another embodiment of a coating
station; FIG. 3D is a schematic diagram of yet another embodiment
of a coating station; FIG. 3E is a schematic diagram of yet another
embodiment of a coating station; FIG. 3F is a schematic diagram of
yet another embodiment of a coating station; FIG. 3G is a schematic
diagram of an embodiment of a coating station comprising a coating
vessel with a die; FIG. 3H is a close side view of the die
illustrated in FIG. 3G; FIG. 3I provides a view of the coating
chamber illustrated FIG. 3G on lines 3I-3I; FIG. 3J illustrates
various examples of cross-sectional shapes of a die orifice; FIG.
3K is a schematic diagram of yet another embodiment of a coating
station.
[0048] FIG. 4A is side view of an elongated conductive body having
portions that are covered by one or more layers of material and
portions that are uncovered; FIG. 4B is a side view of the
elongated conductive body of FIG. 4A after it has been coated with
a layer of coating material.
[0049] FIG. 5 is a flowchart summarizing the steps of one
embodiment of a method for continuously manufacturing analyte
sensors.
[0050] FIGS. 6A and 6B are cross-sectional views through one
embodiment of the elongated conductive body of FIG. 4B on lines
6A-6A and 6B-6B, respectively.
[0051] FIG. 7A illustrates one embodiment of an elongated
conductive body; FIG. 7B illustrates the embodiment of FIG. 7A
after it has undergone laser ablation treatment; FIG. 7C
illustrates another embodiment of an elongated conductive body;
FIG. 7D illustrates the embodiment of FIG. 7C after it has
undergone laser ablation treatment.
[0052] FIG. 8A illustrates one embodiment of an elongated
conductive body; FIG. 8B illustrates the embodiment of FIG. 8A
after it has undergone laser ablation treatment; FIG. 8C
illustrates another embodiment of an elongated conductive body;
FIG. 8D illustrates the embodiment of FIG. 8C after it has
undergone laser ablation treatment.
[0053] FIG. 9A illustrates a recessed region formed with a curved
edge; FIG. 9B illustrates a recessed region formed with a sharp
edge.
[0054] FIG. 10A illustrates one embodiment of a die; FIG. 10B
provides a view of the die on lines 10B-10B of FIG. 10A.
[0055] FIG. 11 illustrates one embodiment of a system that
integrates etching and singulation of the elongated conductive
body.
[0056] It should be understood that the figures shown herein are
not necessarily drawn to scale.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0057] The following description and examples describe in detail
some exemplary embodiments of systems and methods for manufacturing
continuous analyte sensors. It should be understood that there are
numerous variations and modifications of the systems, methods, and
devices 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
[0058] In order to facilitate an understanding of the devices and
methods described herein, a number of terms are defined below.
[0059] 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); biotinidase; biopterin;
c-reactive protein; carnitine; carnosinase; CD4; ceruloplasmin;
chenodeoxycholic acid; chloroquine; cholesterol; cholinesterase;
conjugated 1-.beta. hydroxy-cholic acid; cortisol; creatine kinase;
creatine kinase MM isoenzyme; cyclosporin A; d-penicillamine;
de-ethylchloroquine; dehydroepiandrosterone sulfate; DNA
(acetylator polymorphism, alcohol dehydrogenase, alpha
1-antitrypsin, cystic fibrosis, Duchenne/Becker muscular dystrophy,
glucose-6-phosphate dehydrogenase, hemoglobin A, hemoglobin S,
hemoglobin C, hemoglobin D, hemoglobin E, hemoglobin F, D-Punjab,
beta-thalassemia, hepatitis B virus, HCMV, HIV-1, HTLV-1, Leber
hereditary optic neuropathy, MCAD, RNA, PKU, Plasmodium vivax,
sexual differentiation, 21-deoxycortisol); desbutylhalofantrine;
dihydropteridine reductase; diptheria/tetanus antitoxin;
erythrocyte arginase; erythrocyte protoporphyrin; esterase D; fatty
acids/acylglycines; free .beta.-human chorionic gonadotropin; free
erythrocyte porphyrin; free thyroxine (FT4); free tri-iodothyronine
(FT3); fumarylacetoacetase; galactose/gal-1-phosphate;
galactose-1-phosphate uridyltransferase; gentamicin;
glucose-6-phosphate dehydrogenase; glutathione; glutathione
perioxidase; glycocholic acid; glycosylated hemoglobin;
halofantrine; hemoglobin variants; hexosaminidase A; human
erythrocyte carbonic anhydrase I; 17-alpha-hydroxyprogesterone;
hypoxanthine phosphoribosyl transferase; immunoreactive trypsin;
lactate; lead; lipoproteins ((a), B/A-1, .beta.); lysozyme;
mefloquine; netilmicin; phenobarbitone; 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).
[0060] The term "continuous," as used herein in reference to
analyte sensing, 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 continuous, continual, or
intermittent (e.g., regular) monitoring of analyte concentration,
such as, for example, performing a measurement about every 1 to 10
minutes.
[0061] The term "elongated conductive body," 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 elongated body formed at least in part of a conductive
material and includes any number of coatings that may be formed
thereon. By way of example, an "elongated conductive body" can mean
a bare elongated core (e.g., a conductive metal wire, a
non-conductive polymer rod) or an elongated core coated with one,
two, three, four, five, or more layers of material that may be or
may not be conductive.
[0062] 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 is to take 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.
[0063] The term "sensing region," as used herein, is a broad term,
and is to be given its ordinary and customary meaning to a person
of ordinary skill in the art (and is not to be limited to a special
or customized meaning), and refers without limitation to the region
of a monitoring device responsible for the detection of a
particular analyte.
[0064] 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 diffusion resistance layer and
an enzyme layer. If the sensor is deemed to be the point of
reference and the diffusion resistance layer is positioned farther
from the sensor than the enzyme layer, then the diffusion
resistance layer is more distal to the sensor than the enzyme
layer.
[0065] 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 diffusion resistance
layer and an enzyme layer. If the sensor is deemed to be the point
of reference and the enzyme layer is positioned nearer to the
sensor than the diffusion resistance layer, then the enzyme layer
is more proximal to the sensor than the diffusion resistance
layer.
[0066] The term "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 is not to be limited to a special
or customized meaning), and refers 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, interferents can include compounds with an oxidation
potential that overlaps with that of the analyte to be
measured.
[0067] The terms "membrane system" and "membrane," as used herein,
are broad terms, and are to be given their ordinary and customary
meaning to a person of ordinary skill in the art (and are not to be
limited to a special or customized meaning), and refer without
limitation to a permeable or semi-permeable membrane that can
comprise one or more layers and constructed of materials, which are
permeable to oxygen and may or may not be permeable to an analyte
of interest. In one example, the membrane system comprises an
immobilized glucose oxidase enzyme, which enables an
electrochemical reaction to occur to measure a concentration of
glucose.
[0068] The term "coefficient of variation," as used herein, is a
broad term, and is to be given its ordinary and customary meaning
to a person of ordinary skill in the art (and is not to be limited
to a special or customized meaning), and refers without limitation
to the ratio of the standard deviation of a distribution to its
arithmetic mean. The coefficient of variation can be calculated by
the equation: coefficient of variation=standard deviation/mean.
[0069] 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 300 picoAmps of
current for every 1 mg/dL of glucose analyte.
[0070] The term "current density," 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 per area 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 3 to about 1,000
picoAmps of current per mm.sup.2 of electroactive surface, for
every 1 mg/dL of glucose analyte.
[0071] The term "chamber," 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 partially
or fully enclosed space (e.g., chambers, conduits, channels,
capillaries, tubes, wells, cells, vessels, microchannels, or the
like).
Overview
[0072] FIG. 1A provides a schematic diagram of one embodiment of an
automated, continuous system 100 for manufacturing continuous
analyte sensors, whereby an elongated conductive body 110 is
continuously advanced through a series of stations, each of which
treats the elongated conductive body 110. As shown, these stations
can include, but are not required to include, a coating station 120
for depositing coating material (e.g., insulating, conductive, or
membrane material) onto the elongated conductive body 110, a
thickness control station 130 for removing excess coating material
from the elongated conductive body 110, a drying/curing station 140
for curing the coating material on the elongated conductive body
110, and a thickness measurement station 150 for measuring the
thickness of the elongated conductive body 110 (including any
coatings thereon). During the coating process, the elongated
conductive body 110 can be advanced through this series of stations
repeatedly, i.e., by making multiple repeated passes, until a
preselected thickness has been formed on the elongated conductive
body. The system 100 described herein is merely exemplary, and some
stations may be omitted or replaced by other stations.
[0073] Although not shown in FIG. 1A, in some embodiments, the
system can also include an etching station for removing or
stripping portions of a coated assembly structure on the elongated
conductive body (e.g., to create window regions corresponding to
working electrodes on the elongated conductive body). Etching to
create window regions can be achieved by removing a portion of the
insulating layer, conductive layer, or the like, from the elongated
conductive body, using ablation (e.g., laser skiving), chemical
etching, or other known techniques. Additionally or optionally, the
system can also include a pre-coating treatment station for
pre-cleaning the elongated conductive body before the coating
process, and a post-coating treatment station for post-cleaning
after the coating process. Additionally or optionally, the system
can also include a singulation station for cutting the elongated
conductive body into individual pieces corresponding individual
sensors.
[0074] The system 100 can also be equipped with an automated
control system comprising detector elements, control elements, and
a processor 160. The detector and control elements can be embedded
in the stations and disposed anywhere on or near the pathway of the
elongated conductive body 110. The detector elements are configured
to transmit to the processor 160 signals relating to certain
process conditions of the system 100, such as, for example, the
temperature of the coating solution, the humidity of the atmosphere
immediately around a region of the elongated conductive body which
is undergoing or about to undergo meniscus coating or laser
ablation, the rate at which the elongated conductive body 110 is
advancing, or the last measured thickness of the elongated
conductive body 110. The processor 160 is programmed to process
these input signals and transmit output signals to control
operation of the control elements, e.g., valves, motors, pumps,
agitators, heat lamps, die opening, etc., so that preselected
process conditions for optimum controlled coating processing can be
achieved and maintained. By managing the processing conditions at a
predetermined optimal level, the yield and reproducibility of the
continuous analyte sensors fabricated can be increased.
[0075] In some embodiments, a detector element in the form of a
temperature transducer (e.g., a thermistor) and a control element
in the form of a heat source (e.g., a heat lamp) is disposed at
certain positions along the pathway of the elongated conductive
body 110 to provide temperature control of the elongated conductive
body 110. During operation, if the temperature transducer detects a
temperature that is less than a preselected temperature range, the
temperature transducer is configured to transmit a signal to the
processor 160, which in turn responds by transmitting a signal to
activate the heat source to heat the elongated conductive body 110
to the preselected temperature. In further embodiments, the heat
source is positioned near the entrance of the coating station 120,
so that the elongated conductive body 110 is heated to a
preselected temperature that facilitates the coating process.
Alternatively or additionally, a heat source can be provided near
the exit of the coating station 120 to speed the evaporation of
residual solvent on the elongated conductive body 110.
[0076] In the embodiment shown in FIG. 1A, the system 100 comprises
a transport mechanism 170 for sequentially advancing the elongated
conductive body 110 through the various stations. In this
particular embodiment, the system 100 employs a reel-to-reel
mechanism comprising a motor (not shown in FIG. 1A), a rotatable
supply spool 172, and a rotatable return spool 174. During
operation, the elongated conductive body 110 is attached to both
the supply spool 172 and the return spool 174. Although in some
embodiments, the elongated conductive body is configured to
sequentially advance through the stations in a horizontal or
substantially horizontal arrangement, in other embodiments, a
vertical or substantially vertical arrangement can also be used for
one or more of the stations, for example, to address any
gravity-induced sagging issues with respect to a fresh coating on
the elongated conductive body.
[0077] It is contemplated that any of a variety of transport
mechanisms can be used to advance the elongated conductive body
110. For example, FIGS. 2A and 2B, illustrate a side view and a
front view, respectively, of one embodiment of a transport
mechanism 270 comprising a spool 276, suitable for use as a supply
spool, a return spool, or any other spool employed by the system.
The spool 276 can include a reel 278 mechanically connected to a
motor 271 via a rotatable shaft 273. The motor 271 can be any of a
variety of conventional motors suitable for the applications
contemplated. The reel 278 can be any type of reel upon which the
elongated conductive body can be wound, and can comprise a soft
material, such as silicone rubber, polyurethane, or nylon, for
example, that will not cut away at coatings on the elongated
conductive body and will not allow the elongated conductive body to
slide freely over the reel when the reel is rotated. The diameter
and width of the reel 278 can be varied depending in part on the
dimensions of the elongated conductive body and other design
considerations. In some embodiments, reels with a small width can
be employed where there are tight space constraints. In these
embodiments, coils of the elongated conductive body on the reel can
overlap and touch portions of adjacent coils. In other embodiments,
however, reels having a large width can be desirable, such that the
coils can be arranged to not touch each other. In some embodiments,
reels with large diameters can be used, resulting in a smaller bend
radius, thereby minimizing the risk that materials on the elongated
conductive body will crack or chip off.
[0078] Although in the embodiment shown in FIG. 1A, the system 100
comprises one supply spool 172 and one return spool 174, in other
embodiments the system can comprise any number of spools. For
example, in other embodiments, the system can comprise two, three,
four, five, or more supply spools associated with an equal number
or a different number of return spools.
[0079] In addition, the system can comprise any number of stations.
As illustrated in FIG. 1C, in one exemplary embodiment, the system
can comprise three supply spools 173a, 173b, 173c that provide
three elongated conductive bodies 110a, 110b, 110c, each of which
are wound into a single take-up spool 175. In this particular
embodiment, the system comprises one coating station 120, three
thickness control stations 130a, 130b, 130c, one drying/curing
station 140, and three thickness measurement stations 150a, 150b,
150c. In other embodiments, the system can comprise any number of
station combinations. For instance, in one embodiment, the system
can comprise five coating stations, five thickness control
stations, one drying/curing station, and one thickness measurement
station. In another embodiment, the system can comprise three
coating stations, three thickness stations, three drying/curing
stations, and one thickness measurement station.
[0080] In yet another embodiment, as illustrated in FIG. 1D, the
system can comprise four stations, each of which is configured to
treat multiple portions of the elongated conductive body 110. In
this particular embodiment, the elongated conductive body 110 is
unwound from a supply spool 173 and becomes engaged with a first
guide roller 178 that guides the elongated conductive body 110 to a
coating station 120. Thereafter, the elongated conductive body 110
is advanced through a thickness control station 130, a
drying/curing station 140, and a thickness measurement station 150.
After exiting the measurement station 150, the elongated conductive
body 110 engages a second guide roller 179, by which it is returned
to the first guide roller 178. As illustrated in FIG. 1D, the
elongated conductive body 110 is then advanced through additional
coating station/thickness control station/drying/curing
station/thickness measurement station series/sequences. After
passing through a preselected number of the aforementioned
series/sequences, the elongated conductive body 110 is advanced to
the second guide roller 179, by which it is wound into the take-up
spool 175. Although in the embodiment illustrated in FIG. 1D, the
system is configured to provide five series/sequences of stations;
in other embodiments the system can comprise a different number of
series/sequences. For example, the system can be configured to
provide two, three, five, six, seven, or more series/sequences of
stations.
[0081] As shown in FIGS. 1C and 1D, in some embodiments, the system
can include one or more pulleys or guide rollers 177, 178, 179 for
guiding the elongated conductive body 110 as it advances through
the various stations of the system 100. The guide rollers can be
positioned at any suitable location along the pathway of the
elongated conductive body 110. For example, in one embodiment, a
guide roller can be disposed at a position near the entrance of a
certain station, such as the coating station 120. In another
embodiment, a guide roller can be disposed at a position near the
exit of a certain station, such as a thickness control station 130.
In yet another embodiment, guide rollers can be disposed near both
the entrance and exit of a certain station. In other embodiments,
the system does not use guide rollers, but instead uses the tension
present in the elongated conductive body 110 (derived from the
transport mechanism 170) to guide it along its pathway as it
advances through the various stations.
[0082] In the embodiment shown in FIG. 1A, the pathway of the
elongated conductive body 110 is a cyclical pathway, i.e., the
pathway extends from the supply spool 172 to the return spool 174,
and then extends back to the supply spool 172 from the return spool
174. In other embodiments, however, the pathway may not be
cyclical, but is single directional instead. As illustrated in FIG.
1B, in some of these embodiments, the elongated conductive body 110
is unwound from a supply spool 173 and wound into a take-up spool
175, after which it can be retrieved by an operator and loaded onto
another system for further processing.
[0083] In some embodiments, each of the spools is associated with a
motor configured to drive the spool. In other embodiments, one or
more of the spools is not associated with a motor. For example, in
one embodiment, wherein the pathway is single direction, the
transport mechanism can comprise a take-up spool driven by a motor
to rotate at a preselected speed of rotation, while a corresponding
supply spool is maintained effectively freely rotatable. More
specifically, in this embodiment, whereas rotation of the take-up
spool is actively driven by a motor, rotation of the supply spool
is driven by translational forces from the moving elongated
conductive body, as it is driven by the rotating take-up spool.
When the transport mechanism is activated, the torque exerted by
the take-up spool provides tension to the elongated conductive body
as it unwinds from the supply spool, advances through the various
stations of the system, and eventually winds into the take-up
spool. An increase in the torque exerted by the take-up spool may
also increase the tension present in the elongated conductive
body.
[0084] The tension present in the elongated conductive body 110 can
be measured by any of a variety of tension detectors. For example,
in some embodiments, a tension detector is disposed at various
positions along the pathway of the elongated conductive body 110 to
directly measure its tension. In other embodiments, the tension is
indirectly measured by measuring the torques exerted by the various
spools and calculating the torque differences between the spools.
If the tension is determined to be greater or less than a
preselected value, the tension detector can be configured to
transmit a signal to the processor, which is programmed to
determine whether a problem exists (e.g., a severed elongated
conductive body or one detached from the reel). If the
determination is positive, the system can optionally respond with
an alert or alarm to notify an operator.
[0085] In some of the embodiments described herein, the transport
mechanism 170 is configured to advance the elongated conductive
body 110 at a constant or substantially constant preselected speed.
Selection of the preselected speed can depend in part on design
considerations associated with certain preselected process
conditions (e.g., the preselected viscosity and solids content of
the coating solution, suspension, dispersion, or other liquid
comprising the coating material) that will provide optimal coating
thickness control. In some embodiments, the elongated conductive
body is configured to advance at a preselected speed greater than
about 0.5 cm per minute, or greater than about 10 cm per minute, or
greater than about 25 cm per minute, or greater than about 50 cm
per minute, or even greater than about 250 cm per minute. In
alternative embodiments, a variable-speed transport mechanism can
be used to advance the elongated conductive body at varying speeds.
For example, in some embodiments, the transport mechanism can be
configured to periodically halt the advancement of the elongated
conductive body.
[0086] To confirm that the elongated conductive body is advancing
at the preselected speed, a speed measurement system (e.g., a
vision system) can be employed to measure the elongated conductive
body's actual speed. If the measured speed is not within a certain
range of the preselected speed, the vision system is configured to
transmit a signal to the processor, which in turn can adjust motor
settings in response.
[0087] While the transport mechanism has been described hereinabove
with respect to a reel-to-reel embodiment, the elongated conductive
body 110 may also be advanced through the series of stations with
any of a variety of other transport mechanisms, such as, for
example, a robotic system, a conveyor system, and other like
systems. These other transport mechanisms may be used in
combination with (or as an alternative to) a reel-to-reel system.
For example, in one embodiment, a reel-to-reel system is used to
move the elongated conductive body 110 before it is singulated into
individual pieces 110', and a robotic system is used to move the
individual pieces 110' after the singulation process.
[0088] FIG. 1E illustrates one embodiment of a robotic system 180,
which can range in size from a large device suitable for industrial
scale use to a small device suitable for laboratory bench tops.
Robotic systems may be advantageous in certain instances because
they can provide accurate, precise positioning of the elongated
conductive body 110' in two or three dimensions. In addition, they
are highly flexible and reconfigurable, which can be advantageous
for facilitating the physical transfer of individual pieces to/from
a variety of stations, vessels, containers, chambers, or the like.
Referring back to FIG. 1E, the robotic system 180 comprises an
elongated conductive body holder 182 (e.g., a robot arm) designed
to move an elongated conductive body 110' through variable
programmed motions for performance of a variety of tasks (e.g., for
transferring the elongated conductive body 110' from one coating
vessel 184 to another 186 for different coating applications, and
from one station to another for a variety of treatments). Although
in the embodiment illustrated in FIG. 1E, the elongated conductive
body holder 182 is shown holding a four elongated conductive bodies
110', in alternative embodiments, the elongated conductive body
holder 182 may be capable of holding any number of elongated
conductive bodies 110'.
[0089] In certain embodiments, the elongated conductive body holder
182 is capable of both vertical movements and horizontal movements
(e.g., linear or rotational), thereby allowing not only for
movement between stations, vessels, containers, chambers, or the
like, but also for movement that causes the elongated conductive
body 110' to be submerged or dipped in a coating solution of a
coating vessel 184, or movement that causes the elongated
conductive body 110' to be placed into a curing or drying chamber
188. By using an elongated conductive body holder 182 capable of
various programmed movements, both the number of times and the
length of time that an elongated conductive body 110' is in a
station or is being coated, cured, dried, or treated in a vessel or
chamber can be controlled. By way of example and not to be
limiting, the robot's elongated conductive body holder 182 can be
instructed to dip the elongated conductive body 110' (i.e.,
post-singulation in the form of an individual piece) into the
coating vessel 184 for a plurality of dips, with each dip
interspersed by drying or curing of the coating. While the coating
process has been described hereinabove primarily with respect to a
dipping technique, it should be understood that any of a variety of
other coating techniques, such as, for example, spraying,
electro-depositing, dipping, or casting, may also be used in
addition to (or as an alternative to) dipping. For instance, in
certain embodiments, the elongated conductive body holder 182 is
instructed to place the elongated conductive body 110' in a
position for one or more spraying sessions with a certain coating
material to form a particular layer of the membrane, and then to
dip the elongated conductive body 110' for one or more coating
sessions in a coating solution to form another layer. The length of
time of each dip/spray session and the length of time between each
session can be varied or constant.
[0090] In one embodiment involving the robotic system 180, the
elongated conductive body 110' (in the form of an individual piece)
is dipped one or more times for a predetermined time period in a
pretreatment solution, then dipped one or more times for a
predetermined time period into a solution containing a material
that is to form the electrode and/or interference layer, then
dipped one or more times for a predetermined time period into a
solution containing a material that is to form the enzyme layer,
and then dipped one or more times (for a predetermined time period)
into a solution containing a material that is to form the diffusion
resistance layer. Before, after, and between the dips/sprays, the
elongated conductive body 110' may be treated (e.g., conditioned,
cleaned, cured, dried, etc.) or else maintained under normal
ambient conditions. It should be understood that the process
described above is merely exemplary, and some steps may be omitted
or replaced by other steps.
Elongated Conductive Body
[0091] Any of a variety of elongated conductive bodies can be
treated by the systems and methods described herein. FIG. 7A
illustrates one embodiment of an elongated conductive body
comprising an elongated core 710, a first layer 720 that at least
partially surrounds the core 710, a second layer 730 that at least
partially surrounds the first layer 720, and a third layer 740 that
at least partially surrounds the second layer 730. These layers,
which collectively form a coating assembly structure, can be
deposited onto the elongated core by any of a variety of
techniques, such as, for example, by employing the coating
processes described elsewhere herein. In some embodiments, the
first layer 720 can comprise a conductive material, such as, for
example, platinum, platinum-iridium, gold, palladium, iridium,
graphite, carbon, a conductive polymer, an alloy, and/or the like,
configured to provide suitable electroactive surfaces for one or
more working electrodes. In certain embodiments, the second layer
730 can correspond to an insulator and comprise an insulating
material, such as a non-conductive (e.g., dielectric) polymer, such
as polyurethane, polyimide, polyolefin (e.g., polyethylene), for
example. In some embodiments, the third layer 740 can correspond to
a reference electrode and comprise a conductive material, for
example, a silver-containing material, including, but not limited
to, a polymer-based conducting mixture.
[0092] FIG. 7C illustrates another embodiment of an elongated
conductive body. In this embodiment, in addition to an elongated
core 710, a first layer 720, a second layer 730, and a third layer
740, the elongated conductive body further comprises a fourth layer
750 and a fifth layer 760. In a further embodiment, the first layer
720 and the second layer 730 can be formed of a conductive material
and an insulating material, respectively, similar to those
described in the embodiment of FIG. 7A. However, unlike the
embodiment of FIG. 7A, in this particular embodiment, the third
layer 740 can be configured to provide the sensor with a second
working electrode, in addition to the first working electrode
provided by the first layer 720. In this particular embodiment, the
fourth layer 750 can comprise an insulating material and provide
insulation between the third layer 740 and the fifth layer 760,
which can correspond to a reference electrode and comprise the
aforementioned silver-containing material. It is contemplated that
other similar embodiments are possible. For example, in alternative
embodiments, the elongated conductive body can have 6, 7, 8, 9, 10,
or more layers, each of which can be formed of conductive or
non-conductive material.
[0093] FIGS. 8A and 8C illustrate other embodiments of the
elongated conductive body. In the embodiment illustrated in FIG.
8A, the elongated conductive body comprises three elongated cores
810A, 810B, and 810C located in (e.g., embedded in, coated with)
the insulator 830. FIG. 8C illustrates another embodiment of the
elongated conductive body comprising three insulated conductive
bodies, wherein each insulated conductive body includes an
elongated core 810A, 810B, and 810C coated with an insulator 804A,
804B, and 804C). In some embodiments, the elongated cores (e.g.,
coated with insulator) are bundled together, such as by an elastic
band, an adhesive, wrapping, a shrink-wrap or C-clip, as is known
in the art. In other embodiments, the inner bodies (e.g., coated
with insulator) are twisted, such as into a triple-helix or similar
configuration. In one embodiment, two of the elongated cores (e.g.,
coated with insulator) are twisted together to form a twisted pair,
and then a third core (e.g., with insulator) and/or elongated
conductive body is twisted around the twisted pair. In some
embodiments, the sensor can comprise additional elongated
cores.
[0094] While in some embodiments described herein, the elongated
core is shaped like a wire and has a circular cross-section, in
other embodiments the cross-section of the elongated core can be
oval, square, rectangular, triangular, polyhedral, star-shaped,
C-shaped, T-shaped, X-shaped, Y-Shaped, irregular, or the like. The
elongated core can be formed of any of a variety of suitable
material, such as, platinum, platinum-iridium, gold, palladium,
iridium, graphite, carbon, conductive or non-conductive polymer,
alloys, glass, for example. In some embodiments, the elongated core
comprises an inner core and a first layer, wherein an exposed
electroactive surface of the first layer provides the working
electrode of the continuous analyte sensor being manufactured. For
example, in some embodiments, the inner core comprises stainless
steel, titanium, tantalum and/or a polymer, and the first layer
comprises platinum, platinum-iridium, gold, palladium, iridium,
graphite, carbon, a conductive polymer, and/or an alloy.
[0095] The elongated conductive body can be designed (e.g., by
material selection, by diameter selection, by treatment) to have
certain mechanical properties. For instance, an elongated
conductive body may be designed to meet a certain minimal level of
tensile strength or minimal length of diameter, so that the
elongated conductive body will not be prone to breakage during a
reel-to-reel processing. In some embodiments, the tensile strength
of the elongated conductive body is at least about 200 MPa, or at
least about 500 MPa, or at least about 1,000 MPa, or at least about
2,000 MPa, or even at least about 5,000 MPa. In certain
embodiments, the diameter of the elongated conductive body is at
least about 5 microns, or at least about 15 microns, or at least
about 25 microns, or at least about 50 microns, or at least about
75 microns, or at least about 100 microns, and or even at least
about 200 microns. Other possible embodiments and features of the
elongated conductive body are described in U.S. Provisional
Application No. 61/222,751, the contents of which are incorporated
by reference herein in its entirety.
Workpiece Station
[0096] The material that eventually forms the elongated conductive
body may initially be in the form of one or more workpieces. The
workpiece may be formed of any of a variety of materials, such as,
for example, platinum, platinum-iridium, gold, palladium, iridium,
graphite, carbon, conductive polymers, and alloys or combinations
thereof. In some embodiments, the initial workpiece possesses the
desired dimensions, shapes, and mechanical specifications, and thus
minimal (or no) substantial mechanical or structural changes need
to be made to the workpiece before it is treated and processed
(e.g., coated, dried, etched, singulated, etc.) to form a
continuous analyte sensor. In certain embodiments, the initial
workpiece may already possess the desired shape (e.g., wire, tube,
planar substrate, etc), but not the desired dimensions. In these
embodiments, processing may involve resizing the workpiece to the
desired dimensions.
[0097] In other embodiments, however, the initial workpiece does
not possess any of the above-described desired specifications and
properties, and thus the workpiece has to undergo processing,
whereby the workpiece itself is worked on by machine or hand tools
to impart structural and/or mechanical changes. These changes may
involve, for example, cutting or shaping of the workpiece. They can
also involve the addition of a layer (e.g., coating, cladding,
plating, etc.) that circumscribes the outer surface of the
workpiece. For example, the elongated conductive body may be
fabricated to include a core and a cladding surrounding the core,
both of which are formed from different materials. In some
instances, fabricating the elongated conductive body to have a core
formed with a less expensive, yet strong and flexible material
(e.g., palladium, tantalum, stainless steel, or the like) and a
thin layer of a more expensive material (e.g., platinum) to form
the electroactive surface of the continuous analyte sensor, can
enable a substantial reduction in the material costs required to
build the continuous analyte sensor.
[0098] In one embodiment, fabrication of the elongated conductive
body can be performed by inserting (e.g., by slip fitting) a rod or
wire into a tube, the combination of which forms an initial
structure of an elongated conductive body. The rod or wire may be
formed of any of a variety of materials including, but not limited
to, stainless steel, titanium, tantalum, and/or a polymer. The tube
may be formed of a conductive material, such as, for example,
platinum, platinum-iridium, gold, palladium, iridium, alloys
thereof, graphite, carbon, or a conductive polymer. Alternatively,
instead of using a tube to form the cladding, a layer of conductive
material may be deposited onto the core. Deposition of the
conductive material may be performed by any of a variety of
techniques, such as, for example, chemical vapor deposition,
physical vapor deposition (e.g., sputtering, vacuum deposition),
chemical and electrochemical techniques, dip coating, spray
coating, and optical coating. In some embodiments, the dip coating
and spray coating processes described elsewhere herein may be used
to deposit a coating layer onto the outer surface of the rod or
wire.
[0099] After a cladding/plating/layer has been formed around the
rod or wire, the elongated conductive body can then be passed
through a series of dies to draw down the diameter of the elongated
conductive body from a large diameter to a small diameter. With
each pass through the die (e.g., a diamond die), the
cross-sectional profile of the elongated conductive body is
compressed, and the diameter associated therewith is reduced. It
has been found that while compression tends to increase the tensile
strength of the elongated conductive body, compression also tends
to increase susceptibility of the elongated conductive body to
brittleness, stress cracking, and even breakage. Accordingly, in
some embodiments, an annealing step is used to cause changes in the
mechanical and structural properties of the elongated conductive
body, and more specifically, to relieve internal stresses, refine
the structure by making it homogeneous, and improve cold working
properties. It has also been found that drawing down the diameter
of the elongated conductive body through large numbers of dies in
small incremental steps, instead of through one or a few number of
large incremental step(s), can result in better mechanical and
structural properties. Accordingly, in some embodiments, the
elongated conductive body is passed through a series of dies, with
each successive die having a progressively smaller diameter.
Between each die passing, the elongated conductive body may undergo
an annealing treatment (e.g., by using an annealing oven), through
which the elongated conductive body is softened and its ductility
increased.
[0100] FIG. 10A illustrates one embodiment of a die 1050 used to
compress the elongated conductive body, so as to reduce its
cross-sectional profile. FIG. 10B provides a view of the die on
lines 10B-10B of FIG. 10A. As shown, the die 1050 comprises an
orifice 1020, a front portion 1012, through which an elongated
conductive body 1010 enters the die 1050, and a back portion 1014,
through which the elongated conductive body 1010 exits. The edge
1016 of the front portion 1012 may have a tapering angle .alpha.
defined by the longitudinal axis 1018 of die 1050 and the front
edge 1016. The elongated conductive body 1010 is drawn through a
die 1050 (e.g., diamond die, etc.) and through its orifice 1020. In
some embodiments, the shape and dimensions of the orifice 1020 may
be changed, so that the elongated conductive body can be shaped and
sized to have any desired cross sectional shape and dimensions.
[0101] As the elongated conductive body 1010 is forced through the
die orifice 1050 to impart a shape or to reduce dimensions, the
elongated conductive body 1010 becomes deformed. Drawing the
elongated conductive body 1010 through a die with a large tapering
angle will cause greater compression of the elongated conductive
body 1010 than a die with a smaller tapering angle. Accordingly,
drawing the elongated conductive body 1010 through a series of dies
with large tapering angles may minimize the number of dies that an
elongated conductive body has to be drawn through. However, it has
been found that drawing the elongated conductive body 1010 through
a successive number of dies, each with a smaller tapering angle,
can substantially reduce the risk of breakage, brittleness, stress
cracking, or other mechanical deficiencies that may be imparted on
the elongated conductive body 1010. In some embodiments, the
tapering angle .alpha. of the die is less than about 60 degrees,
sometimes less than about 45 degrees, sometimes less than about 30
degrees, sometimes less than about 30 degrees, and sometimes less
than about 10 degrees.
[0102] With certain embodiments (e.g., an elongated conductive body
in the form of a wire), obtaining and maintaining concentricity of
the elongated conductive body is important. Without concentricity
of the elongated conductive body, subsequent coatings of the
conductive, insulating, and membrane materials may not be uniform,
and consequently performance of the fabricated continuous analyte
sensor may be negatively impacted. For elongated conductive bodies
with circular (or substantially circular) cross-sectional shape, a
lack of uniformity of compressive forces exerted on the
cross-sectional circumference of the elongated conductive body, can
lead to loss of concentricity between the core and the
clad/plate/layer and thereby cause certain portions of the
elongated conductive body to be thicker than other portions.
Accordingly, in some embodiments, the die 1050 is configured to
cause the elongated conductive body 1010 to compress in a way such
that compressive forces exerted on the cross-sectional
circumference of the elongated conductive body are substantially
uniform across the circumference, so that concentricity can be
maintained. The risk of concentricity loss may also be reduced by
use of a positioning system (e.g., a vision system) that may be
disposed near or along the die 1050. The positioning system can be
used to confirm that the elongated conductive body 110 is aligned
correctly during its entry into and exit out of the die 1050, and
that it is moving along a certain predetermined path (e.g., a path
that is perpendicular to the plane defined by the orifice 1020). As
an additional measure to minimize the risk of concentricity loss,
portions of the die 1050, such as the orifice 1020, may be coated
with a lubricant (e.g., oil) to reduce any buildup of friction
associated with the advancement of the elongated conductive body
1010 through the die 1050.
[0103] In some embodiments involving a wire-shaped elongated
conductive body with a substantially circular cross-sectional
profile, the workpiece station comprises a series of dies, which
collectively are capable of reducing the thickness of the elongated
conductive body, while still substantially maintaining the
concentricity of the elongated conduct body. In these embodiments,
the reduction in thickness corresponds to the reduction from an
original elongated conductive body diameter of up to about 250
microns, sometimes up to about 500 microns, sometimes up to about
1,000 microns, and sometimes up to about 2,500 microns, to a final
diameter no less than about 100 microns, sometimes no less than
about 50 microns, sometimes no less than about 25 microns, and
sometimes no less than about 13 microns.
[0104] In addition (or as an alternative) to the treatments
described above, the elongated conductive body can undergo any of a
variety of processing to change its physical (and sometimes
chemical) properties. For example, the elongated conductive body
can undergo annealing, quenching, tempering, drawing, rolling,
normalizing, work hardening, and/or work softening processes, so
that the elongated conductive body acquires certain desired
physical properties.
Etching Station
[0105] The automated, continuous system for manufacturing
continuous analyte sensors may comprise an etching station, whereby
portions of the coated assembly structure is stripped or otherwise
removed. In some embodiments, removal of portions of deposited
layers of coating can be performed to expose the one or more
electroactive surface(s) of the elongated conductive body, thereby
forming recessed regions or window regions/surfaces 420
corresponding to working electrodes. The terms "etching" and
"etched" as used herein are broad terms, and are to be given their
ordinary and customary meaning to a person of ordinary skill in the
art (and are not to be limited to a special or customized meaning),
and refer without limitation to a mechanism for forming one or more
recessed regions within the elongated conducted body. It should be
understood that the terms "etching" and "etched" as used herein is
not limited to chemical etching. Rather, as used herein, "etching"
and "etched" can also include, but are not limited to, techniques,
such as laser etching/ablation/skiving, grit-blasting (e.g., with
sodium bicarbonate or other suitable grit), or the like, that can
be employed to expose certain surfaces of the elongated conductive
body (e.g., the electroactive surfaces corresponding to a
conductive layer or a surface corresponding to an insulating
layer).
[0106] Achieving accuracy and precision with respect to the
particular depth of one or more materials of a coated assembly
which are removed by etching can be important. Without precision
and accuracy (e.g., for certain embodiments involving an elongated
conductive body with a circular or substantially circular
cross-section), uniformity of ablation depth may not be achieved,
and thus concentricity of the elongated conductive body may be
lost. Without achieving and maintaining concentricity with a
proximal layer of the elongated conductive body, any subsequent
(i.e., distal) layers coated over the proximal layer would also not
have concentricity. Loss of concentricity can result in certain
portions of the elongated conductive body being thicker than other
portions, which in turn, can negatively affect sensor performance
(e.g., accuracy).
[0107] In some embodiments, the etching process involves etching a
single layer of material (e.g., etching only an insulating layer or
a conductive layer), but in other embodiments, the etching process
involves etching a plurality of layers (e.g., both a conductive
layer and an insulating layer), such as two, three, four, five, or
more layers. In certain embodiments, portions of the elongated
conductive body can be masked prior to depositing the insulating
layer in order to maintain an exposed electroactive surface
area.
[0108] As noted above, in some embodiments, laser ablation is used
to remove certain layers that have been deposited on the elongated
conductive body. Removal of layers can be performed to expose
electroactive surfaces on the elongated conductive body or else
merely to remove certain insulating or conductive layers or
portions thereof. During the laser ablation process, a laser beam,
which can be pulsed and have a particular wavelength and power
selected to ablate the desired layers, portions, or patterns, is
directed at certain portions of the elongated conductive body to
irradiate the layers in accordance with a preselected pattern. The
pattern can be controlled by the processor to provide for spacings
between the portions of the elongated conductive body that are
ablated. In certain embodiments, these spacings are from about 5 mm
to about 50 mm, or from about 10 mm to about 30 mm, or even from
about 20 mm to about 25 mm.
[0109] The power, duration of the laser pulse, repetition rate of
the laser pulse, and speed of the laser can be varied to control
the speed of the ablation, the amount of material ablated, and the
depth of the ablation. The selected ablation settings may depend on
the shape, size, and other physical properties of the elongated
conductive body. They may also depend on the ablation depth, area,
or shape desired. By controlling the parameters described above,
the risk of the ablation process leaving a substantial amount of
residual ablation debris on the elongated conductive body can be
minimized. In some embodiments relating to laser etching of
polyurethane, the laser beam has a wavelength of from about 100 nm
to about 800 nm, or from about 200 nm to about 300 nm, or from
about 220 nm to about 265 nm, or even from about 245 nm to about
250 nm.
[0110] In certain embodiments, the elongated conductive body is
spun around its longitudinal axis as a laser beam is directed on
the elongated conductive body. In further embodiments, the rotation
rate is greater than about 0.5 revolutions per second, or greater
than about 1 revolution per second, or greater than about 2
revolutions per minute, or greater than about 5 revolutions per
minute, or even greater than about 10 revolutions per minute. The
laser beam can be generated by any of a variety of laser sources,
such as, an excimer laser, YAG laser, CO2 laser, diode laser, for
example. The laser beam energy beam density can be established to
be sufficient to ablate or remove a layer or portion from the
elongated conductive body at a certain predetermined depth and
area, but low enough so as to not damage the layers and materials
outside the predetermined depth and area. The laser beam energy
beam setting can also selected in consideration of the type of
material(s) that is the target of the ablation. In some
embodiments, the laser ablation process involves directing a beam
to remove a small fraction of the total thickness (e.g., a few
microns) of a layer with every pulse or pass. Multiple passes are
then performed, so that the desired ablated depth is achieved. In
certain embodiments, with every pulse or pass, a coating material
corresponding to a depth of 0.5 microns from the surface is
removed, or a coating material corresponding to a depth of 1 micron
from the surface is removed, or a coating material corresponding to
a depth of 1.5 micron from the surface is removed, or a coating
material corresponding to a depth of 2 microns from the surface is
removed, or a coating material corresponding to a depth of 2.5
microns from the surface is removed, or a coating material
corresponding to a depth of 3 microns from the surface is removed,
or a coating material corresponding to a depth of 5 microns from
the surface is removed, or even a coating material corresponding to
a depth of 10 micron from the surface is removed.
[0111] In certain embodiments, instead of using a single laser
beam, multiple laser beams (e.g., two, three, four, or five laser
beams) can be distributed around the elongated conductive body. In
some of these embodiments, the elongated conductive body may not be
configured to rotate during the laser ablation process. Instead,
the plurality of laser beams around the elongated conductive body
can be configured to turn on simultaneously, sequentially, or in
some preselected pattern to remove the desired portion or pattern.
A multi-beam arrangement can be obtained by using multiple laser
sources, or by using one laser source and dividing the laser beam
from this source into multiple branches with use of beamsplitters.
Each of the smaller beams can then be guided or redirected with
individual optical components such as mirrors and lenses, so that
the beams are directed to the elongated conductive body from
different directions or angles. From this, multiple laser beams can
be distributed around a perimeter or circumference of a cross
section of the elongated conductive body to remove a layer all
around the perimeter or circumference of the elongated conductive
body. In alternative embodiments, only certain preselected sections
of a perimeter or circumference of the elongated conductive body
cross section are removed.
[0112] FIG. 7B illustrates one embodiment of the elongated
conductive body of FIG. 7A, after it has undergone laser ablation
treatment. As shown, a window region 722 is formed when the
ablation removes the second and third layers 730, 740, to expose an
electroactive surface of the first conductive layer 720, wherein
the exposed electroactive surface of the first conductive layer 720
correspond to a working electrode. In the embodiment illustrated in
FIG. 7B, the laser ablation treatment of the elongated conductive
body is carried out in steps, as evidenced by the multi-stepped
topography. In a first step, a segment of the third layer 740 is
ablated, and in a second step, a segment of the second layer 730 is
ablated. In this embodiment, the segment of the third layer 740
removed is longer than the segment of the second layer 730 removed.
Accordingly, the risk of third layer material falling onto the
exposed electroactive surfaces of the first layer 720 may be
minimized. Alternatively, in other embodiments, a single step
ablation method can be employed, whereby both the second and third
layers 730, 740, are removed simultaneously.
[0113] FIG. 7D illustrates one embodiment of the elongated
conductive body of FIG. 7C, after it has undergone laser ablation
treatment. Here, two window regions, a first window region 722 and
a second window region 742, are formed, with each window region
having a different depth and corresponding to a working electrode
distinct from the other. As previously described, a multi-step
laser ablation treatment can be employed. In forming the first
window region 722, in a first step, a segment of the third, fourth,
and fifth layers 740, 750, 760 are simultaneously removed. In a
second step, a segment of the second layer 730 is removed to expose
electroactive surfaces of the first conductive layer 720. As
illustrated in FIG. 7D, in this particular embodiment, the segment
of the second layer 720 that is removed is shorter than that
removed of the third, fourth, and fifth layers 740, 750, 760, to
minimize the risk of third, fourth, and fifth layer materials
falling onto the exposed electroactive surfaces of the first layer
720. Similarly, in forming the second window region 744, in a first
step, a segment of the fifth layer 760 is removed, and in a second
step, a segment of the fourth layer 750 shorter than that of the
fifth layer 760 is removed.
[0114] FIGS. 8B and 8D illustrate the elongated conductive bodies
illustrated in FIGS. 8A and 8C, respectively, after they have
undergone ablation treatment. As shown in FIG. 8B, the ablation
treatment removes portions of the insulator from the elongated
conductive body illustrated in FIG. 8A to form a plurality of
window regions, thereby exposing a portion of the elongated cores
810A, 810B, and 810C. In this particular embodiment, window region
822A is formed in the insulator such that a portion of elongated
810A is exposed. Similarly, window region 822B is formed in the
insulator such that a portion of elongated core 810B is exposed. In
other embodiments, the window regions can be staggered and/or
non-staggered along the longitudinal length of the sensor.
[0115] As shown in FIG. 8D, after ablation treatment, the elongated
conductive body illustrated in FIG. 8C is formed with a first
window region 822A configured to expose an electroactive portion of
the first elongated core 810A and with a second window region 822B
configured to expose an electroactive portion of the second
elongated core 810B. In some embodiments, the first and second
elongated cores are configured to function as first and second
working electrodes, respectively, and the third elongated core is
configured to function as a reference or counter electrode.
[0116] In other embodiments, grit blasting is implemented to expose
the electroactive surfaces of an elongated core or conductive
layer. This can be performed by using a grit material that is
sufficiently hard to ablate the coated material, while being
sufficiently soft so as to minimize or avoid damage to the
underlying elongated core or conductive layer. Although a variety
of "grit" materials can be used (e.g., sand, talc, walnut shell,
ground plastic, sea salt, and the like), in some embodiments,
sodium bicarbonate can be used as a grit-material because it is
sufficiently hard to ablate a certain coating (e.g., a
polyurethane, polyimide, or polyethylene insulating layer) without
damaging an underlying core (e.g., platinum conductor). One
additional advantage of sodium bicarbonate blasting includes its
polishing action on certain metals as it strips the polymer layer,
thereby potentially eliminating a cleaning step that might
otherwise be necessary.
[0117] In yet other embodiments, mechanical skiving can be used.
Mechanical skiving can involve using a scribe, a high speed
grinder, mechanical machining, mechanical wheels, or other tools to
impart a recess on the elongated conductive body to expose
electroactive surfaces. In some instances, mechanical skiving can
be advantageous because mechanical skiving typically results in a
recessed region with a curved edge (as illustrated in FIG. 9A),
instead of a recessed region with a sharp edge (as illustrated in
FIG. 9B), as is typically created by a laser ablation process. In
some instances, a recessed region with a curved edge and surface
may provide for better control of coating thickness and/or coating
thickness profile in the window region.
[0118] In yet other embodiments, chemical etching is used to expose
the electroactive surfaces. During the chemical etching process, a
mask, typically formed of an organic film, is deposited onto
selected regions of the elongated conductive body, i.e., the
regions not intended to be etched. The sections between the masked
regions are then etched, and the mask is subsequently removed.
Pre-Coating Treatment Station
[0119] Prior to the coating process, the elongated conductive body
110 can be cleaned to remove organics or other surface contaminants
that may interfere with the coating process. It is contemplated
that any known suitable cleaning method can be used. For example,
in some embodiments, the system uses an ultrasonic cleaning device
comprising a cleaning vessel and a roller or pulley, for guiding
the elongated conductive body inside the cleaning vessel. During
the cleaning process, the cleaning vessel can be filled with a
cleaning solvent, such as isopropanol, acetone, tetrahydrofuran
(THF), or citric acid, for example. Next, the elongated conductive
body is drawn through the cleaning vessel, where it is cleaned by
ultrasonic sound waves and the cleaning solvent, such that when the
elongated conductive body exits the ultrasonic cleaning device, it
is cleaned essentially free of surface contaminants.
[0120] In some embodiments, a drying chamber can be provided
adjacent to the exit of the cleaning vessel. In these embodiments,
as the elongated conductive body exits the drying chamber, it
passes through the drying chamber, where residual solvent on the
surface can be removed, for example, by evaporating the solvent at
a higher rate than that under ambient conditions. Use of a drying
chamber can drive out the solvent using any conventional methods
known, such as by using heat from an evaporator or an inlet supply
of heated inert gas (e.g., nitrogen), or by using vacuum
evaporation, for example.
[0121] In some embodiments, the elongated conductive body can be
cleaned by a plasma device, as an alternative or in addition to the
ultrasonic cleaning device. In these embodiments, the elongated
conductive body can be treated within a vacuum chamber filled with
an inert gas (e.g., Argon), which is electrically charged to
bombard the surface of the elongated conductive body with
sufficient energy for contaminant removal. The resulting
contaminant effluent can then be removed from the drying chamber by
a vacuum pump. Because plasma cleaning does not involve chemical
reactions, under certain conditions, it may remove certain
inorganic contaminants that are not easily removed by ultrasonic
cleaning or chemical processes.
[0122] In certain embodiments, the elongated conductive body can
also undergo surface treatment prior to the coating process to
enhance uniformity of the subsequent coating deposition. The
surface treatment can be carried out by any of a variety of known
techniques. For example, electrostatic charging and/or plasma
surface treatment can be used to modify the surface energy of the
elongated conductive body. Using ionizing gases such as argon or
nitrogen, plasma surface treatment can create highly reactive
species even at low temperatures. Typically, only a few atomic
layers on the surface are involved in the process, so the bulk
properties of the elongated conductive body remain substantially
unaltered by the chemistry. In some instances, plasma surface
treatment may reduce surface contact angles and provide adequate
surface activation for enhanced wetting and adhesive bonding. Other
known surface treatments that can be used include, but are not
limited to, surface washing with a solvent and corona discharge and
UV/ozone treatment.
Coating Station
[0123] FIG. 3A provides a schematic diagram of one embodiment of a
coating station 320. As the elongated conductive body 310 advances
through a meniscus 326 comprising a coating solution formed of a
solvent and a coating material, the elongated conductive body's
surface becomes immersed in the coating solution. As it separates
from the meniscus 326, the elongated conductive body 310 retains a
coating with a layer of substantially uniform thickness on its
outer surface, as illustrated in FIG. 3B. A solid layer of coating
material is then formed on the surface, as the solvent portion of
the coating solution evaporates.
[0124] As shown in the embodiment illustrated in FIGS. 3A and 3B,
the coating station 320 can include a coating vessel 322 with an
opening 324 at its top configured for establishing a meniscus 326.
The coating vessel 322 can be formed of any of a variety of known
inert materials (e.g., ordinary glass or ceramic ware or an inert
polymer such as polyethylene) suitable for the coating processes
contemplated. In addition, the coating vessel 322 can comprise a
collecting section 328 for collecting overflow. In some
embodiments, the coating station 320 can comprise an inert gas
source, which introduces inert gas (e.g., nitrogen, argon) into the
coating station. The inert gas is subsequently removed, so as to
purge certain sections of the coating station. It is contemplated
that in some embodiments the coating station 320 can also comprise
a heat source (e.g., a heat lamp) disposed somewhere near the
meniscus to speed solvent evaporation. In some embodiments, the
environment in or surrounding the coating station 320 can be
controlled. For example, in one system, the coating station 320 can
comprise a temperature control unit disposed near or surrounding
the coating vessel 322 to control the vapor pressure of the
evaporating solvent. Additionally or alternatively, the coating
station 320 can also comprise a humidity control unit configured to
maintain a relatively constant humidity in the coating station 320.
The temperature and humidity inside the coating vessel 320 can each
be independently above, below, or substantially the same as the
ambient temperature and humidity outside of the coating station
320.
[0125] The coating vessel 322 can also comprise various elements
for detecting and controlling certain coating solution conditions,
such as solids content (also commonly referred to as concentration
of coating material), viscosity, and temperature. For example, the
coating vessel 322 can include a temperature detector, a coating
material concentration detector, a viscosity detector, a heat
exchanger, and an agitator (e.g., a stirrer). The processor is
operatively connected to detectors configured to transmit signals
indicative of certain coating solution conditions to the processor.
The processor is also operatively connected to various control
elements (e.g., a heater, stirrer, control valve, etc.) that can be
used to adjust certain coating solution conditions. Collectively,
these various elements and the processor provide a closed-loop
feedback mechanism for controlling coating solution conditions.
[0126] The embodiments described herein are capable of producing
coatings of a precise thickness. This may be achieved in part by
controlling certain coating solution conditions, which in turn
allows for thickness control of the coating layer deposited onto
the elongated conductive body. For example, controlling the
temperature of the coating solution may facilitate thickness
control, given that certain properties of the coating solution,
such viscosity, will vary with temperature changes. As another
example, controlling the viscosity may also facilitate thickness
control, given that a highly viscous coating solution (e.g., with a
high solids content) may sometimes present technical challenges
with respect to thickness uniformity. Additionally, inconsistency
in the viscosity and solids content of the coating solution between
different periods of the coating process may cause inconsistencies
in coating thickness between various segments of the elongated
conductive body.
[0127] During the coating process, a meniscus 326 is established at
the opening 324 at the top of the coating vessel 322, by activating
the pump 321 which drives the solution to continuously circulate at
a precisely controlled rate. To facilitate formation of the
meniscus 326, the opening 324 of the coating vessel 322 can have
any of a variety of shapes and dimensions, depending in part on the
system's preselected process parameters (e.g., the solution used,
the temperature of the solution, the speed at which the elongated
conductive body advances through the coating station, etc.). For
example, in some embodiments, the opening 324 of the coating vessel
322 can be formed with a circular or substantially circular shape,
but in other embodiments, the opening can be formed with a shape
that resembles an ellipse, a polygon (e.g., triangle, square,
rectangle, parallelogram, trapezoid, pentagon, hexagon, octagon),
or the like. The coating vessel 322 can also have any suitable
dimension. For example, in some embodiments, the coating vessel can
have large dimensions, so as to accommodate a plurality (e.g., 3,
4, 5, or 5) of elongated conductive bodies.
[0128] To prevent possible agglomeration of coating material
particles in the coating vessel 322, the coating vessel 322 can be
provided with an agitator 323 (e.g., a stirrer) to ensure that the
coating solution is well mixed. The agitator 323 can also be used
to prevent possible sedimentation of coating material particles at
the bottom of the coating vessel 322. Although not shown in FIG. 3A
or 3B, in some embodiments, the coating vessel can be configured to
be in fluid communication with a solvent source and a coating
material source. During the coating process, if the concentration
of the coating material is measured to be outside a preselected
range, the processor can respond by making adjustments to various
control element setting, for example, by opening a control valve to
introduce a solvent or coating material into the coating vessel, to
return the coating solution to a preselected concentration.
[0129] Referring back to FIG. 3A, in some embodiments, the coating
station 320 comprises a supply vat 325 that continuously feeds
solution into the coating vessel 322 at a precisely controlled,
consistent rate via a line 327 and a pump 329. Accordingly, as the
coating process progresses, the solution held in the coating vessel
322 can be continuously replenished from the supply vat 325. By
maintaining a controlled, consistent rate of flow of the coating
solution from the supply vat 325 to the coating vessel 322, a
continuous, consistent overflow flowing out of the opening 324 is
sustained. In addition, this flow control may allow for control of
the contour and dimensions of the meniscus, which in turn may
provide consistency of coating thickness between different segments
of the elongated conductive body. Overflow flowing out of the
coating vessel can be collected by a collecting section 328, so
that the overflow fluid can be further processed, such as,
recycled, replenished by combining it with solvent and/or coating
material, discarded, etc.
[0130] Although not shown, the supply vat 325 can be connected to
one or more storage tanks that feed coating material and solvent
into the supply vat 325. In some embodiments, the coating solution
can be formed of one coating material and one solvent. In these
embodiments the supply vat 325 can be connected to one storage tank
holding one solvent and another storage tank holding another
coating material. In other embodiments, the coating solution can be
formed of a plurality of coating materials and/or a plurality of
solvents. In these embodiments, the supply vat 325 can be connected
to a plurality of storage tanks each holding a different solvent
and/or a plurality of storage tanks each holding a different
coating material. Similar to the coating vessel 322, the supply vat
325 can also be provided with an agitator (e.g., a stirrer) to
agitate the solution and mix the coating material with the solvent,
to prevent possible agglomeration of coating material particles in
the supply vat 325, and to prevent possible sedimentation of
coating material particles at the bottom of the supply vat 325. In
some embodiments, the supply vat 325 can include a level indicator
for monitoring the level of the coating solution in the supply vat
325. If the fluid level falls below a certain preselected level,
the level indicator is configured to transmit a signal to the
processor, so that new coating solution can be prepared.
[0131] As described elsewhere herein, in some embodiments, the
elongated conductive body selected to undergo the membrane coating
process may already have been coated with one or more layers of one
or more materials (e.g., an elongated core covered with an
insulating layer and/or a conductive layer). Following the
ablation/etching process described elsewhere herein, as illustrated
in FIG. 4A, the surface of the elongated conductive body can have a
stepped topography configuration with a plurality of window regions
420, where portions of the insulating and/or conductive layers were
previously removed. As shown, the window regions 420 are associated
with a diameter 422 (also referred to herein as a window diameter
422) that is less than the diameter 432 associated with the outer
surface 430 of the elongated conductive body 410. Because of the
stepped topography configuration, controlling the coating thickness
on the elongated conductive body 410, particularly the thickness in
the window region 420, presents various technical challenges when
conventional dip coating techniques are used. The embodiments
described herein are configured to overcome these challenges by
providing a mechanism that provides precise control of certain
process parameters.
[0132] As described elsewhere herein, the system may be provided
with a thickness control station 130 configured to control the
coating thickness of certain portions (i.e., the unetched and/or
unablated portions) of the elongated conductive body, by removing
excess coating material from its outer surface 430. However,
because the dimensions of the die orifice of the thickness control
station 130 are constrained by the outer diameter of the elongated
conductive body, a different mechanism can be used to control the
coating thickness and thickness profile of the window regions 420.
As illustrated in FIG. 4B, depositing a coating onto a windows
region 420 with a stepped topography may result in a coating
thickness profile resembling a curve. By controlling certain
process parameters, the embodiments described herein allow for
precise control over the thickness and the thickness profile of the
layers residing in the window regions. To achieve this control, in
some embodiments, the meniscus coating process described herein can
be used, whereby the viscosity of the coating solution, the solids
content of the coating solution, the temperature of the coating
solution, the speed at which the elongated conductive body advances
through the coating station, and/or the flow rate of the coating
solution into the coating vessel are precisely controlled. Each of
the aforementioned process parameters affects the thickness and the
thickness profile of the material coated on the elongated
conductive body. Because the thickness of the coating directly
affects certain properties (e.g., permeability of the membrane
system) of the continuous analyte sensor, achieving tight control
of the thickness may also provide for tight control of these
properties.
[0133] The coating thickness and the uniformity of the thickness
may be controlled by solvent selection. Depending on the
application contemplated, any of a variety of solvents can be used,
each of which is associated with a vapor pressure. The vapor
pressure of a solvent affects the rate at which the solvent
evaporates. Accordingly, solvent selection may affect the thickness
and/or thickness control.
[0134] Control of the viscosity can involve selection of a polymer
forming the coating material, molecular weight selection for the
polymer, control of polymer concentration of the solution, and
solution temperature control. With a low viscosity, a coating may
sometimes considerably sag to the bottom surface of the elongated
conductive body, resulting in a variable layer thickness. In
contrast, with a high viscosity, the coating material may be
difficult to coat onto the elongated conductive body. Accordingly,
it is contemplated that the system can use a coating solution with
an appropriate viscosity which will allow for deposition, but will
yet still provide for control over coating thickness and thickness
profile. The molecular weight of a polymeric coating material may
also affect the viscosity of the coating solution, with viscosity
generally increasing with molecular weight. Viscosity also often
correlates with temperature. Thus, in some embodiments, the
temperature of the coating solution may be controlled so that the
viscosity may be controlled. In some embodiments, the coating
solution is controlled to have a preselected viscosity of from
about 0.1 to about 500 cP, or from about 1 to about 30 cP, or from
about 50 to about 100 cP.
[0135] Control of the solids content of the coating solution may be
achieved by preparing a coating solution with a preselected
concentration level, and sustaining this concentration level by
constantly monitoring the concentration and adjusting as needed. In
some embodiments, the coating solution is controlled to have a
preselected solids content of from about 0.1 to about 60 weight
percent, or from about 1 to about 35 weight percent, and or from
about 5 to about 20 weight percent.
[0136] Control of the coating solution temperature may be achieved
by use of a thermistor and a heating element (e.g., a heat
exchanger). In some embodiments, the coating solution is controlled
to have a preselected temperature from about 20.degree. C. to about
100.degree. C., and or from about 22.degree. C. to about 35.degree.
C.
[0137] Control of the speed at which the elongated conductive body
advances through the coating station can be controlled by the motor
of the transport mechanism. Generally, a slower rate of withdrawal
from the meniscus results in a thicker coating along the surface of
the elongated conductive body. In some embodiments, the elongated
conductive body may be controlled to have a rate of advancement
from about 1 inch/min to about 1,000 ft/min, and or from about 1
ft/min to about 50 ft/min.
[0138] Control of the flow rate of the coating solution into the
coating vessel may be achieved by controlling the output from the
one or more pumps that pump coating solution into the coating
vessel. In some embodiments, the flow rate into the coating vessel
is from about 1 mL/min to about 25 mL/sec, and or from about 3
mL/min to about 7 mL/min.
[0139] Although a meniscus coating process is used coat the
elongated conductive body in some embodiments, it is contemplated
that in other embodiments, other types of coating processes can be
used as an alternative or in addition to the meniscus coating
process. For example, as illustrated in FIG. 3C, in some
embodiments, instead of being configured to advance through a
meniscus, the elongated conductive body 310 can be configured to
advance into the coating vessel 322, where it can dwell for a
preselected period of time. A plurality of rollers or pulley 372,
374, 376 can be disposed near or in the coating vessel 322 to
provide guidance to the elongated conductive body 310 as it
advances along its predetermined path. By precisely controlling
certain process parameters, the embodiment of the system
illustrated in FIG. 3C may be capable of achieving the thickness
control characteristics associated with the meniscus coating
process described elsewhere herein.
[0140] In yet other embodiments, a coating process employing a
vertical arrangement is employed. For example, as illustrated in
FIG. 3D, in some embodiments, the elongated conductive body 310 can
be advanced vertically upwards through a septum 330 disposed at the
bottom of a coating vessel 322, through the coating vessel 322,
whereupon the elongated conductive body 310 is coated with the
coating solution, and then through a thickness control device
(e.g., a die 332 with an orifice 334) whereby excess coating
material is removed. The septum can comprise a sealing member
(e.g., a gasket or a plenum) for preventing the coating solution
from leaking out of the bottom of the coating vessel 332. In these
particular embodiments, the excess coating material falls back into
the coating vessel 322. Similar to other embodiments described
herein, the coating vessel 322 of these embodiments can be
connected to a pump 321 for circulating the coating solution and a
supply vat 325 for feeding coating solution into the coating vessel
322. In further embodiments, the coating vessel 322 can be equipped
with a level indicator for monitoring the level of the coating
solution therein. If the fluid level falls below a certain
preselected level, the level indicator is configured to transmit a
signal to the processor, so that additional coating solution is
drawn from the supply vat 325 to the coating vessel 322 via pump
329.
[0141] Although the methods and systems described herein relate to
dip coating processes, it should be understood that the coating
station can employ any of a variety of other types of coating
processes, such as spray coating or vapor deposition. For example,
in one embodiment, the elongated conductive body is advanced
through a spraying tunnel. While passing through the spraying
tunnel, the elongated conductive body is coated with a coating
material, which can be applied using any of a variety of known
spray coating techniques, such as fog spraying or electrostatic
spraying, for example. In another embodiment, a continuous
manufacturing process is contemplated that utilizes physical vapor
deposition to deposit a coating material. Physical vapor deposition
can be used to coat one or more layers of material onto the
elongated conductive body. It is contemplated that in some
instances, employing physical vapor deposition to coat the
elongated conductive body may result in consistent deposition and
enhanced reproducibility.
[0142] FIG. 3E illustrates one embodiment of a coating station that
employs spray coating. Similar to some of the other embodiments
described herein, in this particular embodiment, the coating
station comprises a circulation pump 321 and a supply vat 325
configured to feed coating solution via a pump 329. In addition,
this embodiment also comprises a nozzle 338 for spraying a coating
solution and a receiving container 336 for collecting coating
solution. During operation, as the elongated conductive body 310 is
advanced through the coating station, it is sprayed with a jet of
coating solution from the nozzle 338. Coating solution that falls
off of the elongated conductive body is collected by the receiving
container 336. From there, the coating solution is pumped via
circulation pump 321 to the nozzle 338. In some embodiments,
periodically (e.g., when the amount of coating solution in the
receiving container 336 is low) coating solution from the supply
vat 325 can also be pumped into the nozzle 338 via pump 329. In
further embodiments, a plurality of nozzles can be provided at
various angles and positions with respect to the pathway of the
elongated conductive body, so as to spray the elongated conductive
body with jets of coating solution from multiple positions and
angles (e.g., from an angle that directs coating solution at the
underside of the elongated conductive body).
[0143] While the transport mechanisms illustrated in FIGS. 3A-3E
involve a reel-to-reel system for moving a long, continuous strand
of elongated conductive body 310 for coating, in other embodiments,
the elongated conductive body being coated may be in the form of
individual pieces 310', e.g., pieces formed after a singulation
process whereby a long, continuous strand of elongated conductive
body 310 is cut into individual pieces 310'. FIG. 3F illustrates
one embodiment of a transport mechanism that can be used to move
elongated conductive bodies 310' that are in the form of individual
pieces. In the embodiment shown in FIG. 3F, the transport system
300 includes a conveyor that supports a plurality of robotic units
380. Each robotic unit 380 comprises a retractable arm 386 secured
to the conveyor 384. The retractable arm 386 comprises an elongated
conductive body holder 388 that supports the elongated conductive
body 310'. Although in the embodiment illustrated in FIG. 3F, the
elongated conductive body holder 388 is shown holding four
elongated conductive bodies 310', in alternative embodiments, an
elongated conductive body holder capable of holding any other
number of elongated conductive bodies 110' may be used instead. As
the retractable arm 386 is extended, the elongated conductive body
310' is moved downwards, and the elongated conductive body 310' is
partially or wholly submerged in a coating solution. After a
predetermined time, the retractable arm is retracted, and the
elongated conductive body 310' is pulled out of the coating
solution. The elongated conductive body 310' is then allowed to dry
as the solvent of the coating solution evaporates. Although not
shown, a heater or dryer may be disposed along the path of the
conveyor or on the robotic unit to accelerate evaporation of the
coating solution.
[0144] As shown in FIG. 3F, the conveyor 384 is designed to advance
the elongated conductive body 310' from one coating vessel 392 to
another coating vessel 394, and then to another coating vessel 396.
Additionally, the conveyor 384 is designed to advance the elongated
conductive body 310' from one station 340 to a coating station 350,
and then to another station 360. Although with the transport system
300 shown in FIG. 3F, the conveyor 384 is shown moving the
elongated conductive body 310' between three stations (including
the coating station 350) and three coating vessels, it should be
understood that in other embodiments, the conveyor 384 may be
configured to move elongated conductive body 310' between any
number of coating vessels and any number of stations.
[0145] In certain embodiments, the step of depositing a coating
material on the elongated conductive body and the step of
controlling the thickness of the coating can be combined. For
example, referring to FIG. 3G, a coating chamber 360 is shown that
includes both a coating vessel 362 for holding a coating solution
364 and a die 366 (e.g., a diamond die) with an orifice 368
configured to control the coating thickness of the elongated
conductive body 310 as it exits the coating chamber 360. FIG. 3H is
a close side view of the die 366 and illustrates a tapering
mechanism of the die. The coating solution 364 may comprise a
solvent and a coating material, such as a conductive material
(e.g., platinum, Ag/AgCl, etc.), an insulating material (e.g.,
polyurethane, polyimide, polyethylene), or a membrane material
(e.g., a material used to form the electrode layer, enzyme layer,
diffusion resistance layer, interference layer, etc.) FIG. 3I
provides a view of the coating chamber 360 on lines 3I-3I of FIG.
3G. It has been found that the tapering mechanism illustrated in
FIG. 3H facilitates a certain fluid dynamic that keeps the
elongated conductive body centered along the longitudinal axis of
the die orifice 368. FIG. 3J illustrates various other non-limiting
examples of cross-sectional shapes of the die orifice 368 that can
be used to mold the elongated conductive body to a desired shape.
It should be understood that the die 366 can not only be used to
coat an elongated conductive body formed of a single core or an
elongated conductive body formed of a plurality of cores, but that
it can also simultaneously coat a plurality of elongated conductive
bodies in parallel.
[0146] The entrance passage of the coating chamber 360 includes an
opening 370 that permits the elongated conductive body 310 to pass
therethrough. A sealing member 342 is used to prevent the coating
solution from leaking out of the opening 370. The sealing member
342 may be any of a variety of seals capable of preventing or
reducing liquid leakage. Seals that can be used include, for
example, o-rings, hydraulic seals, polypak seals, quad rings,
radial shaft seals, v-ring seals, and the like. The coating chamber
360 may include an opening 352 for introduction of the coating
solution into the coating vessel 362. Although the coating solution
is shown in FIG. 3G as being introduced from the top of the coating
vessel 362, it should be understood that in other embodiments the
coating solution may be introduced into coating vessel from other
entry points (e.g., from the side or bottom of the coating vessel)
and by using various other mechanisms (e.g., via a conduit
connected to a pump and a storage tank). The coating chamber 360
may also include a level indicator 344 that communicates with a
control system, so that a predetermined level of coating solution
364 in the coating chamber 360 is maintained.
[0147] In some embodiments, the system is capable of depositing a
coating layer having a substantially uniform thickness along the
outer surface 430 of the elongated conductive body, wherein the
thickness is less than about 35 microns, or less than about 25
microns, or less than about 10 micron, or less than about 5
microns, or less than about 1 microns, or even less than 0.1
microns. In some embodiments, the thickness uniformity of the outer
diameter is better than about .+-.50% of the average thickness, or
better than about .+-.30%, or better than about .+-.10%, or better
than about .+-.5%, or even better than about .+-.1%. In some
embodiments, the coefficient of variation of the outer diameter
thickness is less than about 0.2, or less than about 0.1, or less
than about 0.07, or less than about 0.05, or less than about 0.02,
or even less than about 0.01.
[0148] In addition to being capable of depositing a coating layer
having a substantially uniform thickness along the outer surface of
the elongated conductive body, the system is also capable of
depositing a coating layer with a thickness profile that is
substantially uniform among the plurality of window regions 420 of
the elongated conductive body. More specifically, in some
embodiments, the coating layer deposited onto each window region
can have a thickness profile that is consistent with those of the
other window regions of the elongated conductive body.
[0149] To determine thickness profile uniformity, the mean coating
thickness of each window region can be measured and compared with
those of the other window regions. In some embodiments, wherein the
elongated conductive body comprises 10 or more window regions, the
coefficient of variation (of the 10 or more window regions) of the
mean coating thickness is less than about 0.5, or less than about
0.2, or less than about 0.1, or less than about 0.05, or even less
than about 0.01.
[0150] Thickness profile uniformity may also be determined by
measuring coating thickness at certain locations (e.g., at a first
distance one fifth from one end of the window region, at a second
distance two fifths from one end of the window region, etc.) inside
each window region, and comparing it with other window regions. In
certain embodiments, wherein the elongated conductive body
comprises 10 or more window regions, the coefficient of variation
(of the 10 or more window regions) of the coating thickness at a
first distance one fifth from one end of each of the 10 or more
window regions is less than about 0.3, or less than about 0.2, or
less than about 0.1, or still less than about 0.05, or even less
than about 0.01. In certain embodiments, wherein the elongated
conductive body comprises 10 or more window regions, the
coefficient of variation (of the 10 or more window regions) of the
coating thickness at a second distance two fifths from one end of
each of the 10 or more window regions is less than about 0.3, or
less than about 0.2, or less than about 0.1, or still less than
about 0.05, or even less than about 0.01. In certain embodiments,
wherein the elongated conductive body comprises 10 or more window
regions, the coefficient of variation (of the 10 or more window
regions) of the coating thickness at a third distance three fifths
from one end of each of the 10 or more window regions is less than
about 0.3, or less than about 0.2, or less than about 0.1, or still
less than about 0.05, or even less than about 0.01. In certain
embodiments, wherein the elongated conductive body comprises 10 or
more window regions, the coefficient of variation (of the 10 or
more window regions) of the coating thickness at a fourth distance
fourth fifths from one end of each of the 10 or more window regions
is less than about 0.3, or less than about 0.2, or less than about
0.1, or less than about 0.05, or even less than about 0.01. In
certain embodiments, wherein the elongated conductive body
comprises 10 or more window regions, the coefficient of variation
(of the 10 or more window regions) of the coating thickness at a
midpoint between two ends of each of the 10 or more window regions
is less than about 0.3, or less than about 0.2, or less than about
0.1, or less than about 0.05, or even less than about 0.01.
[0151] By providing the capability of achieving a substantially
uniform thickness profile among the plurality of window regions and
a substantially uniform thickness along the outside surface of the
elongated conductive body, the embodiments also provide the
capability of achieving substantial uniformity with respect to
certain sensor properties, such as sensitivity and current density.
For example, in some embodiments, wherein the elongated conductive
body comprises 10 or more window regions, the coefficient of
variation (of the 10 or more window regions) of in vivo sensor
sensitivity and/or in vitro sensor sensitivity at about 100 mg/dL
glucose concentration is less than about 0.5, or less than about
0.25, or less than about 0.1, or less than about 0.05, or even less
than about 0.01. In certain embodiments, wherein the elongated
conductive body comprises 10 or more window regions, the
coefficient of variation (of the 10 or more window regions) of in
vivo sensor current density and/or in vitro sensor current density
at about 100 mg/dL glucose concentration is less than about 0.5, or
less than about 0.25, or less than about 0.1, or less than about
0.05, or even less than about 0.01.
[0152] Although certain thickness control mechanisms (e.g., die, a
gas knife, etc.) are described elsewhere herein for controlling the
thickness of the coating applied onto the elongated conductive
body, it is contemplated that in some embodiments these control
mechanism may not be necessary. FIG. 3K illustrates one embodiment
of a coating device 390 comprising two absorption pads 398, 399
that are soaked with a solution comprising the coating material.
One or more of absorption pads may be in communication with a
reservoir 378 holding a solution with the coating material. In this
particular embodiment, the two absorption pads are arranged in an
abutting relationship, such that as the elongated conductive body
is advanced in a path along a plane defined by the interface
between the two absorption pads. The solution with the coating
material is applied to the elongated conductive body. By
controlling the concentration gradient that exists at the interface
358, the amount of coating that is applied to the elongated
conductive body 310 can be controlled. Other ways of controlling
the thickness of the elongated conductive body include, but are not
limited to, controlling the surface energy of the elongated
conductive body, controlling the speed at which the elongated
conductive body is advanced, and controlling the viscosity of the
solution comprising the coating material. Accordingly, with
multiple passes through the coating device 390, an elongated
conductive body 310 with a certain preselected thickness of a
coating material can be obtained. The pads may be formed of any
material, such as a fibrous material, that is capable of absorbing
the solution. In addition, although the embodiment illustrated in
FIG. 3K includes two absorption pads, it should be understood that
in other embodiments, a different number of absorption pads (e.g.,
three, four, five, ten, or more) having the same or different
shapes or dimensions can also be used.
Thickness Control Station
[0153] Referring back to FIGS. 1A-1D, After advancing through the
coating station 120, the elongated conductive body 110 is then
advanced to a thickness control station 130. In some embodiments,
the thickness control station 130 comprises a die (not shown)
mounted transverse to the elongated conductive body. As the
elongated conductive body advances through an orifice of the die,
excess coating material is removed to form on the treated surface a
coating layer having a substantially consistent thickness. As
described above, the excess coating material removed is from the
outer surface 430 of the elongated conductive body, and not from
the window surface 420. The dimensions of the die orifice can vary
depending on the type of coating being formed on the elongated
conductive body. With respect to the coating process involving the
insulating layer, the die orifice can have a radius of from about
0.1 to about 25 microns larger than that of the elongated
conductive body without the insulating layer, or from about 5 to
about 15 microns larger, or even from about 10 to about 14 microns
larger. With respect to the coating process involving the
conductive layer, the die orifice can have a radius of from about
0.1 to about 25 microns larger than that of the elongated
conductive body without the conductive layer, or from about 1 to
about 15 microns larger, or even from about 5 to about 10 microns
larger. With respect to the coating process involving the electrode
layer, the die orifice can have a radius from about 0.1 to about 25
microns larger than that of the elongated conductive body without
the electrode layer, or from about 0.2 and 10 microns larger, or
even from about 0.5 to about 1.5 microns larger. With respect to
the coating process involving the interference layer, the die
orifice can have a radius of from about 0.1 to about 25 microns
larger than that of the elongated conductive body without the
interference layer, or from about 0.2 to about 10 microns larger,
or even from about 0.5 to about 1.5 microns larger. With respect to
the coating process involving the enzyme layer, the die orifice can
have a radius of from about 0.1 to about 25 microns larger than
that of the elongated conductive body without the enzyme layer, or
from about 0.2 to about 10 microns larger, or even from about 0.5
to about 1.5 microns larger. With respect to the coating process
involving the diffusion resistance layer, the die orifice can have
a radius of from about 0.1 to about 25 microns larger than that of
the elongated conductive body without the diffusion resistance
layer, or from about 1 to about 15 microns larger, or even from
about 5 to about 10 microns larger.
[0154] While in some embodiments the die orifice has a circular or
substantially circular shape, in other embodiments the die orifice
can have a shape that is oval, square, rectangular, triangular,
polyhedral, star-shaped, C-shaped, T-shaped, X-shaped, Y-Shaped,
irregular, or the like.
[0155] In some embodiments, the thickness control station can
comprise a plurality of dies, each or some of which comprise an
orifice with a shape or dimension different from that of the other
dies. For example, in one embodiment, the thickness control station
can comprise three dies arranged in a series, with each die
comprising a circular orifice, wherein a first die orifice
comprises a larger diameter than that of a second die, and the
second die orifice comprises a larger diameter than that of a third
die. Alternatively, in some embodiments, the thickness control
station can comprise one die with a plurality of orifices formed
therein, with each orifice configured to receive an elongated
conductive body.
[0156] In one embodiment, the die can comprise a plurality of
movable members configured to collectively define the outline of an
orifice, through which the elongated conductive body is configured
to advance. The movable members can be controlled by the processor
to move to different positions and arrangements to form orifices of
different shapes and dimensions. This feature provides the system
with the capability to adjust the shape and dimension of the
orifice to conform to certain preselected process parameters (e.g.,
preselected shape or thickness of the elongated conductive body).
In some embodiments, to make certain that the elongated conductive
body is centered with respect to its entry into the die orifice,
guide rollers or pulleys can be disposed near the entrance and/or
exit of the die, to provide precise guidance to the moving
elongated conductive body.
[0157] As the process progresses, a buildup of coating material may
form in the region of the orifice. To remove this buildup, the
thickness control station can include a solvent source that
periodically or continuously sends solvent to the orifice. In some
embodiments, the thickness control station can comprise a pan for
collecting excess coating material that falls from the elongated
conductive body or the die. The excess coating material may be
discarded or reused if suitable.
[0158] In addition to the die described above, it is contemplated
that other known techniques for removing excess coating material
can also be used. For example, in some embodiments, as an
alternative or in addition to the die, a gas knife, using impinging
jets of inert gas (e.g., nitrogen) can be used.
Drying Curing Station
[0159] As shown in FIG. 1A, the system 100 comprises a drying or
curing station 140 for drying and curing the coating material
deposited onto the elongated conductive body 110. As the elongated
conductive body 110 advances through the drying/curing station 140,
residual solvent on the surface of the elongated conductive body
110 is evaporated. Furthermore, crosslinkable components of the
coating material can be substantially crosslinked. The curing
process can be carried out by any of a variety of conventional
drying techniques, such as by UV, infrared, microwave, x-ray, gamma
ray, or electron beam radiation, whereby radiation is directed at
the coating material, or alternatively by heat, such as by
conduction drying or convection drying, for example, by hot air
convection drying using a hot air convection oven. Depending in
part on the particular coating material used and the coating
thickness, one or more of the above-mentioned techniques may be
used as an alternative (or in addition) to other techniques. For
example, while not wishing to be bound by theory, it is believed
that a high energy radiation curing mechanism (e.g., short
wavelength UV) may sometimes be used when the deposited layer is
thick, because high energy radiation typically penetrates coating
material better than infrared light, and thus may provide more
curing uniformity along the entire thickness of the coated
material. Radiation-based curing may also be used in some
embodiments because it provides tight control over the level of
radiation, thereby allowing for better control of the curing
process. The curing process may take place under a variety of
process conditions. In one embodiment, the drying or curing process
occurs in a curing chamber and/or oven at a temperature of from
about 20.degree. C. to about 500.degree. C., or from about
50.degree. C. to about 150.degree. C., or even from about
200.degree. C. to about 400.degree. C. In some embodiments, the
system can include a humidifier/dehumidifier for maintaining proper
relative humidity in the drying/curing station.
Thickness Measurement Station
[0160] Referring back to the embodiment illustrated in FIG. 1A, the
system 100 includes a thickness measurement station 150 comprising
a thickness measurement sensor or micrometer configured for
measuring the thickness of the elongated conductive body 110 (with
or without coating), as it passes through the thickness measurement
station 150. After obtaining a reading, the micrometer is
configured to transmit to the processor 160 a signal indicative of
the measured thickness. If the measured thickness is determined to
be less than the preselected thickness, the system is configured to
repeat the coating process until a layer having the preselected
thickness is formed.
[0161] It is contemplated that the thickness measurement sensor or
micrometer can be any of a variety of devices capable of measuring
a dimension indicative of a thickness of a coating formed on the
elongated conductive body. For example, in some embodiments, the
micrometer can be an optical micrometer, but in other embodiments
the micrometer can be a gauge device or other similar device
configured to contact the elongated conductive body for thickness
measurement. Optical micrometers that can be used include light
emitting diode (LED) devices, laser devices, or other similar
devices capable of measuring certain elongated bodies (e.g., wires
and webs) at suitable sampling rates. Typically, with an optical
micrometer, the micrometer itself is positioned near the pathway of
the elongated conductive body and configured to measure the
thickness of the elongated conductive body without actually
contacting it.
[0162] In some embodiments, the thickness measurement sensor is
configured to periodically measure the outside diameter of the
elongated conductive body. The thickness measurement sensor can
also be operatively connected to the processor, which is programmed
to compare the latest measurement value of the diameter with a
prior measurement value corresponding to the diameter prior to the
latest coating sequence. The processor may also be programmed to
calculate the thickness of the latest coating by subtracting the
prior measurement value from the latest measurement value. The
thickness of the coated elongated conductive body will of course
progressively increase with each successive layer of coating
material deposited onto the elongated conductive body. Once a
determination has been made as to the layer thickness of a certain
segment of the elongated conductive body, the processor is
programmed to instruct the thickness measurement sensor to measure
another segment of the elongated conductive body as it advances
into the thickness measurement sensor. In some embodiments, the
thickness measurement sensor may be set to make a thickness
measurement about every 100 cm of the elongated conductive body, or
less than about every 50 cm, or less than about every 25 cm, or
still less than about every 10 cm, or less than about every 5 cm,
or less than about every 2.5 cm, or less than about every 1 cm, or
less than about every 1 mm, or even less than about every 100
microns. The measurements made by the thickness measurement sensor
can be for the outer surface of the elongated conductive body, the
window surface, or both. Based upon the signal transmitted from the
thickness measurement sensor, the processor 160 may control certain
parameters of the coating process. For example, if a particular
coating thickness (e.g., thickness of the electrode layer, enzyme
layer, and/or diffusion resistance layer) is measured to be less
than the preselected thickness, the system may be programmed to
repeat the coating process once, twice, or more times, until the
preselected thickness has been achieved.
[0163] Alternatively, in other embodiments, the system may be
programmed to run the coating process for a preselected number of
iterations, instead of programmed to run the coating process
repeatedly until a certain preselected thickness is achieved. In
these embodiments, thickness control can still be achieved because
of the high level of precision of thickness control provided by the
system.
[0164] In some embodiments, the thickness measurement station 150
may not be configured to measure the exact thickness of the
elongated conductive body. Instead, the thickness measurement
station may include a vision system that is configured to detect
certain surface irregularities on the elongated conductive body.
Irregularities can include, but are not limited to, exposed patches
that resemble an undercoating (e.g., an insulating coating
underlying a conductive coating) and that indicate a section of the
elongated conductive body in which coating is very thin or
nonexistent. The exposed patches can show up on the vision system
with a color or reflection that is different than that expected.
After a surface irregularity has been detected, the coating process
can be stopped. Alternatively, the process can be continued, with
the section of the detected surface irregularity recorded, and the
recorded section can be removed in subsequent processing.
Post-Coating Treatment Station
[0165] After the elongated conductive body has been coated with at
least one layer of material, such as a conductive material,
insulating material, or membrane material (e.g., materials that
form the electrode, interference, enzyme, and/or diffusion
resistance layers), with each layer having been determined as
having the preselected thickness, the elongated conductive body can
then be advanced to a post-coating treatment station, where the
elongated conductive body is cleaned and further processed, for
example, through an another surface treatment process (e.g., plasma
treatment). In some embodiments, after singulation of the elongated
conductive body into individual sensors, the ends or tips of the
singulated individual sensors may have various exposed metal
portions not covered by a membrane or an insulating layer. A sensor
formed without a seal covering these end portions may pick up
various levels of unwanted signals. Thus, in some embodiments, the
exposed portions are sealed off using any of a variety of known
techniques, such as, for example, by dipping, spraying, shrink
tubing, or crimp wrapping an insulating, membrane, or other
isolating material onto the sensor tip. In certain embodiments, in
which the sensor tip is capped with a membrane material, the tip
can serve as a working electrode. After the end sealing process,
certain portions (e.g., the back ends) of the singulated sensors
can be etched to expose a conductive material, to provide the
sensors with electrical connection. Alternatively or additionally,
a mechanical connector may be clamped onto the elongated conductive
body's conductive surface, cutting through the membrane in the
process. Thereafter, the sensors can be delivered to other stations
for further processing.
[0166] After the continuous analyte sensors have been completely
built, the sensors are then packaged into containers or boxes for
shipping to a patient, hospital, or retailer. The containers or
boxes may be formed of special materials that are capable of
protecting the sensors from harsh environmental conditions.
Singulation Station
[0167] During any time of the sensor manufacturing process, the
elongated conductive body can be cut for singulation into
individual pieces. For example, in some embodiments, singulation
can be performed before coating of conductive and/or insulating
materials. In other embodiments, singulation can be performed after
coating of the conductive and/or insulating materials, but before
coating of membrane materials. In yet other embodiments,
singulation can be performed after coating of conductive and/or
insulating materials and after coating of membrane materials. Any
of a variety of known cutting systems, such as a system comprising
a hydraulic cutting device, for example, can be used.
[0168] FIG. 11 illustrates one embodiment of a system 1100 that
integrates etching (to remove or strip portions of a coated
assembly structure) and singulation of the elongated conductive
body into individual pieces. In this embodiment, the cutting system
1100 includes a supply spool 1120 which feeds an elongated
conductive body 1110 into an elongated conductive body straightener
1130 (e.g., a wire straightener). The elongated conductive body
1110 is then fed into a rotating mandrel 1140, which rotates the
elongated conductive body 1110. Periodically, an elongated
conductive body gripping device 1150 moves forward and grasps the
end of the elongated conductive body 1110 and then moves backwards
to position the elongated conductive body 1110 for etching by any
of the etching processes described elsewhere herein (e.g., by laser
ablation 1190). Rotation of the elongated conductive body 1110 can
involve a complete rotation (i.e., a rotation of 360 degrees or
more), through which a portion associated with the entire
circumference of the elongated conductive body 1110 is etched.
Alternatively, rotation of the elongated conductive body can be
partial and controlled such that only certain sections associated
with the elongated conduct body's circumference is etched. After
the etching process is completed, a section of the elongated
conductive body 1110 is cut by a cutter 1160. The steps described
are then continuously repeated. It should be understood that the
system described above is merely exemplary, and some components
(e.g., the mandrel 1140 or the etching mechanism) may be omitted or
replaced by other components (e.g., a drying or curing
mechanism).
Sensor Manufacturing Process
[0169] FIG. 5 is a flowchart summarizing the steps of one
embodiment of a method for continuously manufacturing analyte
sensors. In step 510, an elongated conductive body is provided. The
elongated conductive body can be a bare elongated core (e.g., a
metal wire), a cladded elongated core, or a bare or cladded
elongated core coated with one, two, three, four, five, or more
layers of material. Although not shown in FIG. 5, in some
embodiments, step 510 can be preceded by one or more steps, wherein
the above-described elongated conductive body (as shown in FIG. 4A)
is built by coating an elongated core (e.g., a wire) with one or
more layers of material (e.g., an insulating layer and a conductive
layer) to form a coated assembly structure, and then removing
portions of the coated assembly structure. For example, in one
embodiment, the elongated core is advanced through a coating
station/thickness control station/drying/curing station/thickness
measurement station series/sequence, whereby it is coated with an
insulating material. The series/sequence may be repeated until an
insulating layer having a preselected thickness has been deposited,
as measured by the thickness measurement sensor. The elongated
conductive body is then advanced through a coating
station/thickness control station/drying/curing station/thickness
measurement station sequence, whereby it is coated with a
conductive material. Again, the sequence may be repeated until a
conductive layer having a preselected thickness has been deposited.
After the insulating and conductive layers have been deposited onto
the elongated core, the elongated conductive body can then be
advanced to an etching station, where portions of the coated
assembly structure is stripped or otherwise removed (e.g., to
expose the electroactive surfaces of the elongated core, thereby
creating window regions corresponding to electroactive surface
areas).
[0170] In step 520, the elongated conductive body is advanced
through a pre-coating treatment station, where it is cleaned with a
solvent to remove surface contaminants. In some embodiments, an
additional drying step can be provided to evaporate any residual
solvents left on the surface of the elongated conductive body.
[0171] In step 530, the elongated conductive body is advanced
through a coating station, where a coating solution comprising a
solvent and a coating material (e.g., a material to form a
conductive layer, insulating layer, or a membrane) is deposited
onto the elongated conductive body. The layers that may form the
membrane system are described in greater detail below. As the
solvent portion of the coating solution evaporates, a solid layer
of the coating material is formed on the elongated conductive body.
In some embodiments, the coating solution is deposited by a
meniscus coating process, whereby the elongated conductive body is
advanced through a meniscus established at an opening of a coating
vessel. The meniscus coating process described herein provides the
system with the capability of precisely controlling the thickness
and thickness profile of the coating deposited.
[0172] In step 540, the elongated conductive body is advanced
through a thickness control station, where excess coating material
can be removed to form on the treated surface a layer of coating
having a substantially consistent thickness. In some embodiments,
the coating station and the thickness control station may be
integrated into one station.
[0173] In step 550, the elongated conductive body is advanced
through the drying or curing station, where it may be dried under
ambient conditions or heated to remove residual solvent on the
surface of the elongated conductive body. In certain embodiments,
at the drying or curing station, crosslinkable components of the
coating material are substantially crosslinked. The curing process
can be carried out by any of a variety of conventional drying
techniques including, but not limited to, by UV, infrared,
microwave, x-ray, gamma ray, or electron beam radiation, or by
heat.
[0174] In step 560, the elongated conductive body is advanced
through the thickness measurement station, where a measurement is
made of the thickness of the elongated conductive body, and a
signal indicative of the measurement is transmitted to the
processor. The processor then compares the measured thickness with
a preselected thickness. If the measured thickness is determined to
be less than the preselected thickness, the system is programmed to
repeat the coating process until a layer having the preselected
thickness is formed.
[0175] In step 570, after being coated with multiple layers of
material (e.g., insulating, conductive, electrode, interference,
enzyme, and/or diffusion resistance material), with each layer
having the preselected thickness, the elongated conductive body is
advanced into the post-coating treatment station, where it can be
cleaned and/or undergo further treatment. Thereafter, the
individual sensors can be delivered to other stations for further
processing.
[0176] It should be understood that the method described above is
merely exemplary, and some steps may be omitted or replaced by
other steps. Furthermore, although the steps of the method are
described in a particular order, the various steps need not be
performed sequentially or in the order described. For example, in
some embodiments, an elongated conductive body is provided, as
indicated by step 510. Thereafter, it undergoes processing, as
indicated by steps 520, 530, 540, 550, and 560, whereby a coating
forming a first layer (e.g., an insulating layer) with a
preselected thickness is deposited on the elongated conductive
body. The coating process (i.e., the sequence formed of steps 520,
530, 540, 550, and 560) can be repeated several times, with each
passing sequence resulting in a successive layer (e.g., a second
layer comprising an enzyme layer, a third layer comprising a
diffusion resistance layer, etc.) with a preselected thickness
being deposited onto the elongated conductive body. After the
preselected layers have been deposited, the elongated conductive
body can then be transferred to a station for post-coating
treatment, as indicated by step 570.
[0177] To demonstrate the method described in FIG. 5, an example is
provided herein describing one embodiment of coating polyurethane
(an insulating material) onto the outer conductive surface of an
elongated conductive body. Although the material described in this
example is polyurethane, it should be understood that other
insulating materials (e.g., polyethylene, polyimide, etc.) may be
also be used in accordance with the method described herein.
[0178] In step 510, an elongated conductive body is provided which
has an outer conductive layer formed of platinum and an inner core
formed of another material (e.g., stainless steel, titanium,
tantalum, glass, polymeric material, non-conductive material,
etc.). In an alternative embodiment, the entire elongated
conductive body may be monolithic and formed of a conductive
material, such as platinum, platinum-iridium, gold, palladium,
iridium, graphite, carbon, conductive polymers, and combinations
thereof.
[0179] Next, in step 520 the elongated conductive body is treated
(e.g., washed with alcohol or treated with plasma). In some
embodiments, an adhesion promoter may be applied to the outer
surface of the elongated conductive body. The adhesion promoter may
be used to cause surface reaction to improve adhesion of the
polyurethane to the conductive surface of the elongated conductive
body, and thereby reduce the risk of delamination. The adhesion
promoters, in a non-limiting embodiment, can be monomers, oligomers
and/or polymers. Such materials include, but are not limited to,
organometallics such as silanes, (e.g., mercapto silanes, acrylate
or methacrylate functional silanes, vinyl silanes, amino silanes,
epoxy silanes, isocyanate silanes, fluoro silanes, and alkyl
silanes), siloxanes, titanates, zirconates, aluminates, metal
containing compounds, zirconium aluminates, hydrolysates thereof
and mixtures thereof. In one embodiment, silane is used as an
adhesion promoter, and it is used as a component of a solution. In
a further embodiment, the solution comprises from about 90% to 98%
organic solvent (e.g., ethanol, tetrahydrofuran), about 1% to 5%
water, and about 1 to 5% silane onto the outer surface of the
elongated conductive body. The solvents may then be removed by air
drying and/or by using an oven.
[0180] Thereafter, in step 530, the polyurethane is coated onto the
elongated conductive body using any of the coating techniques
described elsewhere herein, such as a meniscus coating method. The
polyurethane coating is then dried or cured. In certain
embodiments, the polyurethane may have a thickness of from about 5
microns to about 50 microns, or from about 12 microns to about 25
microns, or even from about 18 microns to about 23 microns. Excess
coating materials of polyurethane are then removed by use of a die,
in accordance with step 540. The cycle from step 510 to step 550
can then be repeated until a preselected thickness of the
polyurethane layer has been achieved.
[0181] To further demonstrate the method described in FIG. 5,
another example is provided herein. This particular example
describes one embodiment of coating a platinum material onto the
elongated core or an Ag/AgCl material (i.e., a conductive material)
onto the polyurethane layer described in the example above.
Although the materials used in this example are platinum, Ag/AgCl,
and polyurethane, it should be understood that other conductive
materials and insulating materials may also be used in accordance
with the method described herein.
[0182] With respect to coating of Ag/AgCl onto the polyurethane,
the coating material can involve an Ag/AgCl solution or paste which
can be purchased from commercially available sources or
alternatively prepared to have certain specified properties.
Typically, an AgCl layer is consumed during a period when the
Ag/AgCl electrode is used as a cathode. Accordingly, by controlling
the composition, thickness, or other properties of the Ag/AgCl
layer, the effective lifespan of a sensor (i.e., the period of time
that it can function properly) can be controlled by the
manufacturing method. The silver grain and the silver chloride
grain can have any of a variety of shapes, such as a shape similar
to a sphere, plate, flake, a polyhedron, or combinations
thereof.
[0183] In some embodiments, the silver grain in the Ag/AgCl
solution or paste can have an average particle size associated with
a maximum particle dimension that is less than about 100 microns,
or less than about 50 microns, or less than about 30 microns, or
less than about 20 microns, or less than about 10 microns, or even
less than about 5 microns. The silver chloride grain in the Ag/AgCl
solution or paste can have an average particle size associated with
a maximum particle dimension that is less than about 100 microns,
or less than about 80 microns, or less than about 60 microns, or
less than about 50 microns, or less than about 20 microns, or even
less than about 10 microns. The silver grain and the silver
chloride grain may be incorporated at a ratio of the silver
chloride grain:silver grain of from about 0.01:1 to 2:1 by weight,
and sometimes from about 0.1:1 to 1:1. The silver grains and the
silver chloride grains are then mixed with a carrier (e.g., a
polyurethane) to form a solution or paste. In certain embodiments,
the Ag/AgCl component comprises from about 10% to about 65% by
weight of the total Ag/AgCl solution or paste, or from about 20% to
about 50% by weight of the total Ag/AgCl solution or paste, or even
from about 23% to about 37% by weight of the total Ag/AgCl solution
or paste. In some embodiments, the Ag/AgCl solution or paste has a
viscosity (under ambient conditions) that is from about 1 to about
500 centipoise, or from about 10 to about 300 centipoise, or even
from about 50 to about 150 centipoise.
[0184] Prior to the coating step 530, an elongated conductive body
is provided in step 510. In one embodiment associated with coating
of platinum onto the elongated core, the elongated conductive body
is only an elongated core. In one embodiment associated with
coating of Ag/AgCl onto polyurethane, the elongated conductive body
has an outer conductive layer formed of platinum with an inner
elongated core formed of another material (e.g., stainless steel,
titanium, tantalum, polymeric material, non-conductive material,
etc.). Disposed over the platinum layer is a layer of polyurethane
deposited using the method described in the example above. In
alternative embodiments, the entire elongated conductive body may
be monolithic and formed of a conductive material, such as
platinum, platinum-iridium, gold, palladium, iridium, graphite,
carbon, conductive polymers, and combinations thereof.
[0185] Next, in step 520 the elongated conductive body is treated
(e.g., washed with an alcohol wash, treated with plasma, or corona
treatment). Similar to the example described above regarding the
coating of polyurethane, an adhesion promoter may optionally be
applied to the polyurethane to improve the adhesion of the
polyurethane to the Ag/AgCl material being deposited or of the
elongated core material (e.g., stainless steel, tantalum) to the
platinum material being deposited.
[0186] Thereafter, in step 530, the platinum solution or Ag/AgCl
solution or paste is coated onto the elongated conductive body
using any of the coating techniques described elsewhere herein. In
one embodiment, the coating chamber 360 illustrated in FIG. 3G is
used to perform the coating step 530. In addition, the die 366 in
the coating chamber is used to perform the step 540 of removing
excess platinum, Ag/AgCl, or other material from the elongated
conductive body. In one embodiment associated with coating of
platinum onto the elongated core, the coated platinum layer may
have a thickness of from a thickness corresponding to a layer
formed from a few platinum atoms to about 200 microns, or from
about 1 micron to about 10 microns, or even from about 3 microns to
about 5 microns. In one embodiment associated with the coating of
Ag/AgCl onto the elongated core, the coated Ag/AgCl layer can have
a thickness of from about 0.5 microns to about 30 microns, or from
about 1 micron to about 20 microns, or even from about 5 microns to
about 15 microns. The cycle from step 510 to step 550 is then be
repeated until a preselected thickness of the platinum layer or
Ag/AgCl layer has been achieved. It is contemplated that the ratio
of the thickness of the Ag/AgCl layer to the thickness of the
polyurethane layer can be controlled, so as to allow for a certain
error margin (e.g., an error margin associated with the etching
process) that would not result in a defective sensor (e.g., due to
a defect resulting from an etching process that cuts into a depth
more than intended, thereby unintentionally exposing an
electroactive surface). This ratio may be different depending on
the type of etching process used, e.g., whether it is laser
ablation, grit blasting, chemical etching, or some other etching
method. For laser ablation, the ratio of the thickness of the
Ag/AgCl layer to the thickness of the polyurethane layer can be
from about 1:5 to about 1:1, or from about 1:3 to about 1:2.
Membrane System
[0187] The membrane systems described herein can be formed using
the systems and methods described above, and are suitable for use
with implantable sensors in contact with a biological fluid. For
example, the membrane system can be utilized with sensors for
measuring analyte levels in a biological fluid, such as sensors for
monitoring glucose levels for individuals having diabetes. In some
embodiments, the analyte-measuring sensor is a continuous sensor. A
wide variety of sensor configurations are contemplated with respect
to sensor placement. For example, in some embodiments, the sensor
can be configured for transdermal (e.g., transcutaneous) placement,
but in other embodiments the sensor can be configured for
intravascular placement, subcutaneous placement, intramuscular
placement, or intraosseous placement. The sensor can use any method
to provide an output signal indicative of the concentration of the
analyte of interest; these methods can include, for example,
invasive, minimally invasive, or non-invasive sensing
techniques.
[0188] Although some of the description that follows is directed at
glucose-measuring devices, the membrane systems described herein
are not limited to use in devices that measure or monitor glucose.
Rather, 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, drug delivery devices, and the like.
[0189] FIG. 6A is a cross-sectional view through one embodiment of
the elongated conductive body of FIG. 4B on line 6A-6A,
illustrating one embodiment of the membrane system 600. The
cross-section illustrated in FIG. 6A corresponds to the window
surface of the elongated conductive body. As described above, the
window surface can correspond to a working electrode formed in
part, for example, by removing a portion of the insulating material
and conductive material from an electroactive surface the elongated
conductive body by ablation, etching, or other like techniques.
FIG. 6B is a cross-sectional view through the elongated conductive
body of FIG. 4B on line 6B-6B.
[0190] In the particular embodiment shown in FIGS. 6A and 6B, the
membrane system 600 comprises an electrode layer 620, interference
layer 630, enzyme layer 640, and a diffusion resistance layer 650,
located around the core 610 of the elongated conductive body. It
should be understood that any of the layers described herein, e.g.,
the electrode, interference, enzyme, or diffusion resistance layer,
may be omitted. In addition, it should be understood the membrane
system can have any of a variety of layer arrangements, with some
arrangements having more or less layers than other arrangements.
For example, in some embodiments, the membrane system can comprise
one interference layer, one enzyme layer, and two diffusion
resistance layers, but in other embodiments, the membrane system
can comprise one electrode layer, one enzyme layer, and one
diffusion resistance layer. Additionally, it should be understood
that although the exemplary embodiments illustrated in FIGS. 6A and
6B involve circumferentially extending membrane systems covering an
elongated conductive body with a circular cross-section, the
membranes described herein can be applied to any planar or
non-planar surface and an elongated conductive body with any
variety of cross-sectional shapes, such as oval, square,
rectangular, triangular, polyhedral, star-shaped, C-shaped,
T-shaped, X-shaped, Y-Shaped, irregular, or the like, for example.
As shown, the portion of the elongated conductive body
corresponding to the section illustrated in FIG. 6B comprises an
additional conductive layer 670 and an insulating layer 660 that
separates the core 610 from the conductive layer 670.
[0191] In some embodiments, one or more layers of the membrane
system can 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),
polyamides, polyimides, polystyrenes, 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.
[0192] In some embodiments, one or more layers of the membrane
system are formed from a silicone polymer. In further embodiments,
the silicone composition can have molecular weight of from about
50,000 to about 800,000 g/mol. It has been found that having the
polymers formed with this molecular weight range facilitates the
preparation of cross-linked membranes that provide the strength,
tear resistance, stability, and toughness advantageous for use in
vivo.
[0193] In some embodiments, the silicone polymer is a liquid
silicone rubber that may be vulcanized using a metal- (e.g.,
platinum), peroxide-, heat-, ultraviolet-, or other
radiation-catalyzed process. In some embodiments, the silicone
polymer is a dimethyl- and methylhydrogensiloxane copolymer. In
some embodiments, the copolymer has vinyl substituents. In some
embodiments, commercially available silicone polymers can be used.
For example, commercially available silicone polymer precursor
compositions can be used to prepare the blends, such as described
below. In one embodiment, MED-4840 available from NUSIL.RTM.
Technology LLC is used as a precursor to the silicone polymer used
in the blend. MED-4840 consists of a 2-part silicone elastomer
precursor including vinyl-functionalized dimethyl- and
methylhydrogensiloxane copolymers, amorphous silica, a platinum
catalyst, a crosslinker, and an inhibitor. The two components can
be mixed together and heated to initiate vulcanization, thereby
forming an elastomeric solid material. Other suitable silicone
polymer precursor systems include, but are not limited to, MED-2174
peroxide-cured liquid silicone rubber available from NUSIL.RTM.
Technology LLC, SILASTIC.RTM. MDX4-4210 platinum-cured biomedical
grade elastomer available from DOW CORNING.RTM., and Implant Grade
Liquid Silicone Polymer (durometers 10-50) available from Applied
Silicone Corporation.
[0194] In some embodiments, one or more layer of the membrane
system is formed from a blend of a silicone polymer and a
hydrophilic polymer. By "hydrophilic polymer," it is meant that the
polymer has a substantially hydrophilic domain in which aqueous
substances can easily dissolve. It has been found that use of such
a blend may provide high oxygen solubility and allow for the
transport of glucose or other such water-soluble molecules (for
example, drugs) through the membrane. In one embodiment, the
hydrophilic polymer comprises both a hydrophilic domain and a
partially hydrophobic domain (e.g., a copolymer), whereby the
partially hydrophobic domain facilitates the blending of the
hydrophilic polymer with the hydrophobic silicone polymer. In one
embodiment, the hydrophobic domain is itself a polymer (i.e., a
polymeric hydrophobic domain). For example, in one embodiment, the
hydrophobic domain is not a simple molecular head group but is
rather polymeric.
[0195] The silicone polymer for use in the silicone/hydrophilic
polymer blend can be any suitable silicone polymer, include those
described above. The hydrophilic polymer for use in the
silicone/hydrophilic polymer blend can be any suitable hydrophilic
polymer, including but not limited to components such as
polyvinylpyrrolidone (PVP), polyhydroxyethyl methacrylate,
polyvinylalcohol, polyacrylic acid, polyethers such as polyethylene
glycol or polypropylene oxide, and copolymers thereof, including,
for example, di-block, tri-block, alternating, random, comb, star,
dendritic, and graft copolymers (block copolymers are discussed in
U.S. Pat. No. 4,803,243 and U.S. Pat. No. 4,686,044). In one
embodiment, the hydrophilic polymer is a copolymer of poly(ethylene
oxide) (PEO) and poly(propylene oxide) (PPO), such as PEO-PPO
diblock copolymers, PPO-PEO-PPO triblock copolymers, PEO-PPO-PEO
triblock copolymers, alternating block copolymers of PEO-PPO,
random copolymers of ethylene oxide and propylene oxide, and blends
thereof, for example. In some embodiments, the copolymers can be
optionally substituted with hydroxy substituents. Commercially
available examples of PEO and PPO copolymers include the
PLURONIC.RTM. brand of polymers available from BASF.RTM.. Some
PLURONIC.RTM. polymers are triblock copolymers of poly(ethylene
oxide)-poly(propylene oxide)-poly(ethylene oxide) having the
general molecular structure:
HO--(CH.sub.2CH.sub.2O).sub.x--(CH.sub.2CH.sub.2CH.sub.2O).sub.y--(CH.su-
b.2CH.sub.2O).sub.x--OH
wherein the repeat units x and y vary among various PLURONIC.RTM.
products. The poly(ethylene oxide) blocks act as a hydrophilic
domain allowing the dissolution of aqueous agents in the polymer.
The poly(propylene oxide) block acts as a hydrophobic domain
facilitating the blending of the PLURONIC.RTM. polymer with a
silicone polymer. In one embodiment, PLURONIC.RTM. F-127 is used
having x of approximately 100 and y of approximately 65. The
molecular weight of PLURONIC.RTM. F-127 is approximately 12,600
g/mol as reported by the manufacture. Other PLURONIC.RTM. polymers
include PPO-PEO-PPO triblock copolymers (e.g., PLURONIC.RTM. R
products). Other suitable commercial polymers include, but are not
limited to, SYNPERONICS.RTM. products available from
UNIQEMA.RTM..
[0196] The membrane system of some embodiments can comprise at
least one polymer containing a surface-active group. 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 are inclined to migrate towards a surface of a
membrane formed thereof. 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.
[0197] Base polymers useful for certain embodiments can include any
linear or branched polymer on the backbone structure of the
polymer. Suitable base polymers can include, but are not limited
to, epoxies, polyolefins, polysiloxanes, polyethers, acrylics,
polyesters, carbonates, and polyurethanes, wherein polyurethanes
can 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 can 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 layer of the continuous sensor.
[0198] In some embodiments, a base polymer synthesized to have
hydrophilic segments can be used to form at least a portion of the
membrane system. For example, a linear base polymer including
biocompatible segmented block polyurethane copolymers comprising
hard and soft segments can be used. It is contemplated that
polyisocyanates can be used for the preparation of the hard
segments of the copolymer and may be aromatic or aliphatic
diisocyanates. The soft segments used in the preparation of the
polyurethane can be derived from a polyfunctional aliphatic polyol,
a polyfunctional aliphatic or aromatic amine, or the like that can
be useful for creating permeability of the analyte (e.g., glucose)
therethrough, and can 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).
[0199] Alternatively, in some embodiments, the membrane system can
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), 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 can
be used to yield a blend with desired glucose, oxygen, and
interference permeability properties. For example, in some
embodiments, the membrane can comprise 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 can be used instead. In some
of the embodiments involving use of PVP, the PVP portion of the
polymer blend can comprise from about 5% to about 50% by weight of
the polymer blend, or from about 15% to 20%, or even 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 can be from about 25,000 daltons to about 5,000,000
daltons, or from about 50,000 daltons to about 2,000,000 daltons,
or even greater than 5,000,000 daltons, for example, from 6,000,000
daltons to about 10,000,000 daltons.
[0200] Coating solutions that include at least two surface-active
group-containing polymers can 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 coated onto to the surface of the elongated conductive body
using the coating process described elsewhere herein. The coating
can then be cured under high temperature (e.g., about
50-150.degree. C.), as the elongated conductive body is advanced
through the drying/curing station.
[0201] 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.
[0202] Described below are examples of layers that can be coated
onto the elongated conductive body to form the membrane system.
Diffusion Resistance Layer
[0203] In some embodiments, the membrane system comprises a
diffusion resistance layer, which may be disposed more distal to
the elongated core than the other layers. A molar excess of glucose
relative to the amount of oxygen exists 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)). Accordingly, without a
semipermeable membrane situated over the enzyme layer to control
the flux of glucose and oxygen, a linear response to glucose levels
can sometimes 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. The diffusion resistance layer
serves to address these issues by controlling the flux of oxygen
and other analytes (for example, glucose) to the underlying enzyme
layer.
[0204] The diffusion resistance layer can include a semipermeable
membrane that controls the flux of oxygen and glucose to the
underlying enzyme layer, thereby rendering 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 layer. In some
embodiments, the diffusion resistance layer exhibits an
oxygen-to-glucose permeability ratio of approximately 200:1, but in
other embodiments the oxygen-to-glucose permeability ratio can 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)).
[0205] In some embodiments, the diffusion resistance layer 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 can 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 that can be used 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 some embodiments. The material that
forms the basis of the hydrophobic matrix of the diffusion
resistance layer can be any of those known in the art that is
suitable 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.
[0206] In some embodiments, the diffusion resistance layer can
comprise a blend 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 diffusion resistance layer can 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 can be used instead. In some of the embodiments involving
the use of PVP, the PVP portion of the polymer blend can comprise
from about 5% to about 50% by weight of the polymer blend, or from
about 15% to 20%, and or 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 can be from
about 25,000 daltons to about 5,000,000 daltons, or from about
50,000 daltons to about 2,000,000 daltons, or even greater than
about 5,000,000 daltons, e.g., from 6,000,000 daltons to about
10,000,000 daltons.
[0207] In certain embodiments, the thickness of the diffusion
resistance layer can be from about 0.05 microns or less to about
200 microns or more. In some of these embodiments, the thickness of
the diffusion resistance layer can 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 diffusion resistance layer 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.
[0208] The description herein of the diffusion resistance layer is
not intended to be applicable only to the diffusion resistance
layer; rather the description can also be applicable to any other
layer of the membrane system, such as the enzyme layer, electrode
layer, or interference layer, for example.
Enzyme Layer
[0209] In some embodiments, the membrane system comprises an enzyme
layer, which may be disposed more proximal to the elongated core
than the diffusion resistance layer. The enzyme layer comprises a
catalyst configured to react with an analyte. In one embodiment,
the enzyme layer is an immobilized enzyme layer including glucose
oxidase. In other embodiments, the enzyme layer can be impregnated
with other oxidases, for example, alcohol dehydrogenase, 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.
[0210] In some embodiments, the catalyst (enzyme) can be
impregnated or otherwise immobilized into the diffusion resistance
layer such that a separate enzyme layer is not required (e.g.,
wherein a unitary layer is provided including the functionality of
the diffusion resistance layer and enzyme layer). In some
embodiments, the enzyme layer is formed from a polyurethane, for
example, aqueous dispersions of colloidal polyurethane polymers
including the enzyme.
[0211] In some embodiments, the thickness of the enzyme layer can
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 layer is 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, 4, or 5 microns to about
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 19.5, 20, 25,
or 30 microns, or 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.
[0212] It should be understood that the description herein of the
enzyme layer is not intended to be applicable only to the enzyme
layer; rather the description can also be applicable to any other
layer of the membrane system, such as the diffusion resistance
layer, electrode layer, or interference layer, for example.
Electrode Layer
[0213] In some embodiments, the membrane system comprises an
electrode layer, which may be disposed more proximal to the
elongated core than any other layer. The electrode layer is
configured to facilitate electrochemical reaction on the
electroactive surface and can include a semipermeable coating for
maintaining hydrophilicity at the electrochemically reactive
surfaces of the sensor interface. In other embodiments, the
functionality of the electrode layer can be incorporated into the
diffusion resistance layer, so as to provide a unitary layer that
includes the functionality of the diffusion resistance layer,
enzyme layer, and/or electrode layer.
[0214] The electrode layer can enhance the stability of an adjacent
layer by protecting and supporting the material that makes up the
adjacent layer. The electrode layer 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 layer
may also protect against pH-mediated damage that can result from
the formation of a large pH gradient between the substantially
hydrophobic interference layer and the electrodes due to the
electrochemical activity of the electrodes.
[0215] In one embodiment, the electrode domain includes hydrophilic
polymer film (e.g., a flexible, water-swellable, hydrogel) having a
"dry film" thickness of from about 0.05 microns or less to about 20
microns or more, or from about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3,
0.35, 0.4, 0.45, 0.5, 1, 1.5, 2, 2.5, 3, or 3.5 microns to about 4,
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 19.5
microns, or even from about 3, 2.5, 2, or 1 microns, or less, to
about 3.5, 4, 4.5, or 5 microns or more. "Dry film" thickness
refers to the thickness of a cured film cast from a coating
formulation by standard coating techniques.
[0216] In certain embodiments, the electrode layer can 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, wherein the polyurethane polymer
undergoes aggregation with a water-soluble carbodiimide (e.g.,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)) in the
presence of polyvinylpyrrolidone and cured at a moderate
temperature of about 50.degree. C.
[0217] 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 XW-121 and XW-123; and a
polyester-polyurethane backbone containing carboxylate groups,
identified as XW-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, can be used.
[0218] In some embodiments, the electrode layer is formed from a
hydrophilic polymer that renders the electrode layer substantially
more hydrophilic than an overlying layer (e.g., interference layer,
enzyme layer). Such hydrophilic polymers can 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.
[0219] In some embodiments, the electrode layer is formed primarily
from a hydrophilic polymer, and in some of these embodiments, the
electrode layer 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) can be used
to form the electrode layer. 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.
[0220] In certain embodiments, the electrode layer 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 can
be used in some embodiments.
[0221] It is contemplated that in certain embodiments, the
hydrophilic polymer used may not be crosslinked, but in other
embodiments, crosslinking may be used and achieved by any of a
variety of methods, for example, by adding a crosslinking agent. In
some embodiments, a polyurethane polymer can be crosslinked 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 crosslinking can be achieved by irradiation at a
wavelength sufficient to promote crosslinking between the
hydrophilic polymer molecules, which is believed to create a more
tortuous diffusion path through the layer.
[0222] 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 crosslinker is included. In one embodiment, a
coating formulation can contain from about 6 to about 20 dry weight
percent, or about 8 dry weight percent, PVP; from about 3 to about
10 dry weight percent, or about 5 dry weight percent cross-linking
agent; and from about 70 to about 91 weight percent, or 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.
[0223] In some embodiments, underlying the electrode layer 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 layer. It
is contemplated that certain embodiments can 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.
[0224] It should be understood that the description herein of the
electrode layer is not intended to be applicable only to the
electrode layer; rather the description can also be applicable to
any other layer of the membrane system, such as the diffusion
resistance layer, enzyme layer, or interference layer, for
example.
Interference Layer
[0225] In some embodiments, the membrane system may comprise an
interference layer configured to substantially reduce the
permeation of one or more interferents into the electrochemically
reactive surfaces. The interference layer may be configured to be
substantially 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
diffusion resistance layer (e.g., via a surface-active
group-containing polymer of the diffusion resistance layer), a
separate interference layer may not be used.
[0226] In some embodiments, the interference layer is formed from a
silicone-containing polymer, such as a polyurethane containing
silicone, or a silicone polymer. While not wishing to be bound by
theory, it is believed that, in order for an enzyme-based glucose
sensor to function properly, glucose would not have to permeate the
interference layer, where the interference layer is located more
proximal to the electroactive surfaces than the enzyme layer.
Accordingly, in some embodiments, a silicone-containing
interference layer, comprising a greater percentage of silicone by
weight than the diffusion resistance layer, can be used without
substantially affecting glucose concentration measurements. For
example, in some embodiments, the silicone-containing interference
layer can comprise a polymer with a high percentage of silicone
(e.g., from about 25%, 30%, 35%, 40%, 45%, or 50% to about 60%,
70%, 80%, 90% or 95%).
[0227] In one embodiment, the interference layer can include ionic
components incorporated into a polymeric matrix to reduce the
permeability of the interference layer to ionic interferents having
the same charge as the ionic components. In another embodiment, the
interference layer can include a catalyst (for example, peroxidase)
for catalyzing a reaction that removes interferents.
[0228] In certain embodiments, the interference layer can include a
thin membrane that is designed to limit diffusion of certain
species, for example, those greater than 34 kD in molecular weight.
In these embodiments, the interference layer permits certain
substances (for example, hydrogen peroxide) that are to be measured
by the electrodes to pass through, and prevents passage of other
substances, such as potentially interfering substances. In one
embodiment, the interference layer is constructed of polyurethane.
In an alternative embodiment, the interference layer comprises a
high oxygen soluble polymer, such as silicone.
[0229] In some embodiments, the interference layer is formed from
one or more cellulosic derivatives. In general, cellulosic
derivatives can include polymers such as cellulose acetate,
cellulose acetate butyrate, 2-hydroxyethyl cellulose, cellulose
acetate phthalate, cellulose acetate propionate, cellulose acetate
trimellitate, or blends and combinations thereof.
[0230] In some alternative embodiments, other polymer types that
can be utilized as a base material for the interference layer
include polyurethanes, polymers having pendant ionic groups, and
polymers having controlled pore size, for example. In one such
alternative embodiment, the interference layer includes a thin,
hydrophobic membrane that is non-swellable and restricts diffusion
of low molecular weight species. The interference layer is
permeable to relatively low molecular weight substances, such as
hydrogen peroxide, but restricts the passage of higher molecular
weight substances, including glucose and ascorbic acid.
[0231] It is contemplated that in some embodiments, the thickness
of the interference layer can be from about 0.01 microns or less to
about 20 microns or more. In some of these embodiments, the
thickness of the interference layer can 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 layer can 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.
[0232] It should be understood that the description herein of the
interference layer is not intended to be applicable only to the
interference layer; rather the description can also be applicable
to any other layer of the membrane system, such as the diffusion
resistance layer, enzyme layer, or electrode layer, for
example.
Therapeutic Agents
[0233] A variety of therapeutic (bioactive) agents can be used with
the analyte sensor system. In some embodiments, the therapeutic
agent is an anticoagulant for preventing coagulation within or on
the sensor. In some embodiments, the therapeutic agent is an
antimicrobial, such as but not limited to an antibiotic or
antifungal compound. In some embodiments, the therapeutic agent is
an antiseptic and/or disinfectant. Therapeutic agents can be used
alone or in combination of two or more agents. The therapeutic
agents can be dispersed throughout the material of the sensor. In
some embodiments, the membrane system can include a therapeutic
agent that is incorporated into a portion of the membrane system,
or which is incorporated into the device and adapted to diffuse
through the membrane.
[0234] There are a variety of systems and methods by which the
therapeutic agent can be incorporated into the membrane system. In
some embodiments, the therapeutic agent is incorporated at the time
of manufacture of the membrane system. For example, the therapeutic
agent can be blended prior to curing the membrane system. In other
embodiments, the therapeutic agent is incorporated subsequent to
membrane system manufacture, for example, by coating, imbibing,
solvent-casting, or sorption of the bioactive agent into the
membrane system. Although the therapeutic agent can be incorporated
into the membrane system, in some embodiments the therapeutic agent
can be administered concurrently with, prior to, or after insertion
of the device intravascularly, for example, by oral administration,
or locally, for example, by subcutaneous injection near the
implantation site. In some embodiments, a combination of
therapeutic agent incorporated in the membrane system and
therapeutic agent administration locally and/or systemically can be
used.
[0235] To the extent publications and patents or patent
applications incorporated by reference herein contradict the
disclosure contained in the specification, the specification is
intended to supersede and/or take precedence over any such
contradictory material.
[0236] 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; adjectives such as "known",
"conventional", "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;
and use of terms like "preferred", "desired", or "desirable", and
terms of similar meaning should not be understood as implying that
certain features are critical, essential, or even important to the
structure or function of the invention, but instead as merely
intended to highlight alternative or additional features that may
or may not be utilized in a particular embodiment of the invention.
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.
[0237] 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 should not be read to mean that the narrower
case is intended or required in instances where such broadening
phrases may be absent.
[0238] 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.
[0239] 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.
* * * * *