U.S. patent application number 09/810917 was filed with the patent office on 2002-01-10 for collection assemblies, laminates, and autosensor assemblies for use in transdermal sampling systems.
This patent application is currently assigned to Cygnus, Inc.. Invention is credited to Conn, Thomas E., Ford, Russell, Soni, Pravin L., Tierney, Michael J., Vijayakumar, Prema.
Application Number | 20020004640 09/810917 |
Document ID | / |
Family ID | 22190994 |
Filed Date | 2002-01-10 |
United States Patent
Application |
20020004640 |
Kind Code |
A1 |
Conn, Thomas E. ; et
al. |
January 10, 2002 |
Collection assemblies, laminates, and autosensor assemblies for use
in transdermal sampling systems
Abstract
The invention relates generally to consumable components of a
device used for continually or continuously measuring the
concentration of target chemical analytes present in a biological
system. More particularly, the invention relates to collection
assemblies, laminate structures, and autosensor assemblies, which
are used in connection with a transdermal sampling device. In one
aspect, the invention includes autosensor assemblies which include
laminate structures, electrode assemblies, and support trays. One
important application of the invention involves an autosensor
assembly for use in a blood glucose monitoring device.
Inventors: |
Conn, Thomas E.; (Palo Alto,
CA) ; Ford, Russell; (San Francisco, CA) ;
Soni, Pravin L.; (Sunnyvale, CA) ; Tierney, Michael
J.; (San Jose, CA) ; Vijayakumar, Prema;
(Fremont, CA) |
Correspondence
Address: |
Barbara G. McClung
Cygnus Inc.
Intellectual Property Dept.
400 Penobscot Drive
Redwood City
CA
94063
US
|
Assignee: |
Cygnus, Inc.
|
Family ID: |
22190994 |
Appl. No.: |
09/810917 |
Filed: |
March 16, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09810917 |
Mar 16, 2001 |
|
|
|
09309616 |
May 11, 1999 |
|
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|
60085345 |
May 13, 1998 |
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Current U.S.
Class: |
604/20 ; 600/347;
600/365 |
Current CPC
Class: |
A61B 5/1486
20130101 |
Class at
Publication: |
604/20 ; 600/347;
600/365 |
International
Class: |
A61N 001/30; A61B
005/00 |
Claims
What is claimed is:
1. A collection assembly, for use in a iontophoretic sampling
device useful to monitor a selected analyte or derivatives thereof
present in a biological system, said collection assembly comprising
a) a collection insert layer comprised of an ionically conductive
material having first and second portions, each portion having
first and second surfaces, b) a mask layer comprised of a material
that is substantially impermeable to the selected analyte or
derivatives thereof, wherein the mask layer (i) has inner and outer
faces and said outer face provides contact with said biological
system and the inner face is positioned in facing relation with the
first surface of each collection insert, (ii) defines first and
second openings that are aligned with the first and second portions
of the collection insert layer, (iii) each opening exposes at least
a portion of the first surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang; and
(c) a retaining layer having (i) inner and outer faces wherein the
inner face is positioned in facing relation with the second surface
of each collection insert, (ii) defines first and second openings
that are aligned with the first and second portions of the
collection insert layer, (iii) each opening exposes at least a
portion of the second surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang.
2. The collection assembly of claim 1, wherein (i) the inner face
of the mask layer contacts the inner face of the retaining layer,
and (ii) the overhangs provided by the mask and retaining layers
sandwich the collection insert layer portions therebetween.
3. The collection assembly of claim 2, wherein the perimeter of the
mask layer is greater than the perimeter of the retaining layer
thus forming an overhang of the mask layer relative to the
perimeter of the retaining layer.
4. The collection assembly of claim 1, wherein said collection
insert layer further comprises a gasket layer and the gasket layer
is between the mask layer and the retaining layer.
5. The collection assembly of claim 4, wherein (i) said gasket
layer has first and second parts, each part comprising a
substantially planar material having a top face, a bottom face, and
an opening extending between said top and bottom faces, wherein the
top face of each gasket layer part contacts the inner face of the
mask layer, the bottom face of each gasket layer part contacts the
inner face of the retaining layer, and the openings of the first
and second parts are each axially aligned with the first and second
openings in the mask and retaining layers, and (ii) within each
gasket layer part a collection insert is arranged and substantially
fills each opening in each gasket layer part.
6. The collection assembly of claim 5, wherein each opening of the
retaining layer exposes the entire second surface of each
collection insert, thus creating a gasket.
7. The collection assembly of claim 1, wherein the mask layer is
comprised of a material selected from the group consisting of high
density polyethylene (HDPE), low density polyethylene (LDPE), very
low density polyethylene (VLDPE), polyethylene copolymers,
thermoplastic elastomers, silicon elastomers, polyurethane (PU),
polypropylene (PP), (PET), nylon, flexible polyvinylchloride (PVC),
natural rubber, synthetic rubber, and combinations thereof.
8. The collection assembly of claim 3, wherein the retaining layer
is comprised of a material selected from the group consisting of
high density polyethylene (HDPE), low density polyethylene (LDPE),
very low density polyethylene (VLDPE), polyethylene copolymers,
thermoplastic elastomers, silicon elastomers, polyurethane (PU),
polypropylene (PP), (PET), nylon, flexible polyvinylchloride (PVC),
natural rubber, synthetic rubber, and combinations thereof.
9. The collection assembly of claim 3, wherein at least one of the
collection insert layer portions comprises glucose oxidase.
10. The collection assembly of claim 1, wherein the collection
insert layer comprises a hydrogel.
11. The collection assembly of claim 1, wherein the retaining layer
has an outer face that is adhesive.
12. The collection assembly of claim 1, wherein the outer face of
the retaining layer and exposed surfaces of the collection layer
insert contact a first surface of a first removable liner.
13. The collection assembly of claim 12, wherein said first
removable liner has a plow-fold shape.
14. The collection assembly of claim 1, wherein the outer face of
the mask layer and exposed surfaces of the collection layer insert
contact a first surface of a second removable liner.
15. The collection assembly of claim 1, further comprising a first
removable liner attached to the outer face of the retaining layer,
and a second removable liner attached to the outer face of the mask
layer.
16. The collection assembly of claim 1, wherein the mask layer has
an outer face that is adhesive.
17. The collection assembly of claim 1, wherein the retaining layer
has an outer face that is adhesive.
18. The collection assembly of claim 1, wherein the first and
second openings in the mask layer are positioned in the collection
assembly such that they are aligned with the first and second
openings in the retaining layer and thereby define a plurality of
flow paths through the collection assembly.
19. The collection assembly of claim 1, wherein the mask and
retaining layers are contacted with each other along a central
portion which separates the first and second openings in each layer
such that said first and second portions of the collection insert
are individually sandwiched between the mask and retaining
layers.
20. The collection assembly of claim 1, where said analyte is
glucose.
21. A laminate comprising any one of the collection assemblies of
any of claims 1 through and including 20.
22. A sealed package containing the laminate of claim 21.
23. The sealed package of claim 22, further comprising a hydrating
insert.
24. An autosensor assembly for use in a iontophoretic sampling
device useful to monitor an analyte present in a biological system,
said autosensor assembly comprising, (I) a collection assembly said
collection assembly comprising, a) a collection insert layer
comprised of an ionically conductive material having first and
second portions, each portion having first and second surfaces, b)
a mask layer comprised of a substantially planar material that is
substantially impermeable to the selected analyte or derivatives
thereof, wherein the mask layer (i) has inner and outer faces and
said outer face provides contact with said biological system and
the inner face is positioned in facing relation with the first
surface of each collection insert, (ii) defines first and second
openings that are aligned with the first and second portions of the
collection insert layer, (iii) each opening exposes at least a
portion of the first surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang; (c)
a retaining layer having (i) inner and outer faces wherein the
inner face is positioned in facing relation with the second surface
of each collection insert, (ii) defines first and second openings
that are aligned with the first and second portions of the
collection insert layer, (iii) each opening exposes at least a
portion of the second surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang; and
(d) where the first and second openings in the mask layer are
positioned in the collection assembly such that they are aligned
with the first and second openings in the retaining layer and
thereby define a plurality of flow paths through said collection
assembly; (II) an electrode assembly having an inner and outer
face, the inner face comprising first and second bimodal
electrodes, wherein the first and second bimodal electrodes are
aligned with the first and second openings in the retaining layer
of the collection assembly; and (III) a support tray that contacts
the outer face of the electrode assembly.
25. The autosensor assembly of claim 24, wherein the collection
assembly (i) the inner face of the mask layer contacts the inner
face of the retaining layer, and (ii) the overhangs provided by the
mask and retaining layers sandwich the collection insert layer
portions therebetween.
26. The autosensor assembly of claim 25, wherein the perimeter of
the mask layer is greater than the perimeter of the retaining
layer.
27. The autosensor assembly of claim 24, wherein the mask layer is
comprised of a material selected from the group consisting of high
density polyethylene (HDPE), low density polyethylene (LDPE), very
low density polyethylene (VLDPE), polyethylene copolymers,
thermoplastic elastomers, silicon elastomers, polyurethane (PU),
polypropylene (PP), (PET), nylon, flexible polyvinylchloride (PVC),
natural rubber, synthetic rubber, and combinations thereof.
28. The autosensor assembly of claim 24, wherein the retaining
layer is comprised of a material selected from the group consisting
of high density polyethylene (HDPE), low density polyethylene
(LDPE), very low density polyethylene (VLDPE), polyethylene
copolymers, thermoplastic elastomers, silicon elastomers,
polyurethane (PU), polypropylene (PP), (PET), nylon, flexible
polyvinylchloride (PVC), natural rubber, synthetic rubber, and
combinations thereof.
29. The autosensor assembly of claim 24, wherein at least one of
the collection insert layer portions comprises glucose oxidase.
30. The autosensor assembly of claim 24, wherein the collection
insert layer comprises a hydrogel.
31. The autosensor assembly of claim 24, wherein the retaining
layer has an outer face that is adhesive.
32. The autosensor assembly of claim 24, wherein the outer face of
the retaining layer and exposed surfaces of the collection layer
insert contact a first surface of a first removable liner.
33. The autosensor assembly of claim 32, wherein said first
removable liner has a plow-fold shape.
34. The autosensor assembly of claim 24, wherein the outer face of
the mask layer and exposed surfaces of the collection layer insert
contact a first surface of a second removable liner.
35. The autosensor assembly of claim 24, further comprising a first
removable liner attached to the outer face of the retaining layer,
and a second removable liner attached to the outer face of the mask
layer.
36. The autosensor assembly of claim 24, wherein the mask layer has
an outer face that is adhesive.
37. The autosensor assembly of claim 24, wherein the retaining
layer has an outer face that is adhesive.
38. The autosensor assembly of claim 24, wherein the mask and
retaining layers are contacted with each other along a central
portion which separates the first and second openings in each layer
such that said first and second portions of the collection insert
are individually sandwiched between the mask and retaining
layers.
39. The autosensor assembly of claim 24, wherein said analyte is
glucose.
40. The autosensor assembly of any of claims 24 through and
including 39, wherein said collection assembly is a laminate.
41. A sealed package containing the autosensor assembly of claim
40.
42. The sealed package of claim 41, further comprising a hydrating
insert.
43. A sealed package containing the autosensor assembly of any of
claims 24 through and including 39.
44. The sealed package of claim 43, further comprising a hydrating
insert.
45. A collection assembly for use in a iontophoretic sampling
device useful to monitor a selected analyte, or derivatives
thereof, present in a biological system, said collection assembly
comprising a) a mask layer comprised of a substantially planar
material that is substantially impermeable to the selected analyte
or derivatives thereof, where said mask layer has inner and outer
faces and said outer face provides contact with said biological
system; b) a collection insert layer comprised of an ionically
conductive material having first and second surfaces, and c) said
mask and collection insert layers are configured such that (i) at
least a portion of said collection insert is exposed to provide
contact with the biological system, and (ii) flow of the analyte
through the first surface of the collection insert layer from the
biological system is prevented by the mask layer for any portion of
the first surface of the collection insert layer that is in contact
with the inner face of the mask layer.
46. An autosensor assembly comprising (a) the collection assembly
of claim 45, (b) an electrode assembly having an inner face
comprising an electrode and an outer face, where the inner face of
the electrode assembly and the collection assembly are aligned to
define a plurality of flow paths through said collection assembly,
and (c) a support tray that contacts said outer face of the
electrode assembly.
47. A sealed package containing the autosensor assembly of claim
46.
48. The sealed package of claim 47, further comprising a hydrating
insert.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is related to U.S. Provisional Patent
Application Serial No. 60/085,345, filed May 13, 1998, from which
priority is claimed under 35 USC .sctn.119(e)(1), and which
application is incorporated herein by reference in its
entirety.
TECHNICAL FIELD OF THE INVENTION
[0002] Novel laminate structures, collection assemblies, and
autosensor assemblies for use in a sampling device are described.
The invention relates generally to consumable components of a
device used for continually or continuously measuring the
concentration of target chemical analytes present in a biological
system. The laminates, collection assemblies, and autosensor
assemblies are used in a transdermal sampling device that is placed
in operative contact with a skin or mucosal surface of a biological
system to obtain a chemical signal associated with an analyte of
interest.
BACKGROUND OF THE INVENTION
[0003] A number of diagnostic tests are routinely performed on
humans to evaluate the amount or existence of substances present in
blood or other body fluids. These diagnostic tests typically rely
on physiological fluid samples removed from a subject, either using
a syringe or by pricking the skin. One particular diagnostic test
entails self-monitoring of blood glucose levels by diabetics.
[0004] Diabetes is a major health concern, and treatment of the
more severe form of the condition, Type I (insulin-dependent)
diabetes, requires one or more insulin injections per day. Insulin
controls utilization of glucose or sugar in the blood and prevents
hyperglycemia which, if left uncorrected, can lead to ketosis. On
the other hand, improper administration of insulin therapy can
result in hypoglycemic episodes, which can cause coma and death.
Hyperglycemia in diabetics has been correlated with several
long-term effects of diabetes, such as heart disease,
atherosclerosis, blindness, stroke, hypertension and kidney
failure.
[0005] The value of frequent monitoring of blood glucose as a means
to avoid or at least minimize the complications of Type I diabetes
is well established. Patients with Type II (non-insulin-dependent)
diabetes can also benefit from blood glucose monitoring in the
control of their condition by way of diet and exercise.
[0006] Conventional blood glucose monitoring methods generally
require the drawing of a blood sample (e.g., by finger prick) for
each test, and a determination of the glucose level using an
instrument that reads glucose concentrations by electrochemical or
calorimetric methods. Type I diabetics must obtain several finger
prick blood glucose measurements each day in order to maintain
tight glycemic control. However, the pain and inconvenience
associated with this blood sampling, along with the fear of
hypoglycemia, has led to poor patient compliance, despite strong
evidence that tight control dramatically reduces long-term diabetic
complications. In fact, these considerations can often lead to an
abatement of the monitoring process by the diabetic. See, e.g., The
Diabetes Control and Complications Trial Research Group (1993) New
Engl. J. Med. 329:977-1036.
[0007] Recently, various methods for determining the concentration
of blood analytes without drawing blood have been developed. For
example, U.S. Pat. No. 5,267,152 to Yang et al. describes a
noninvasive technique of measuring blood glucose concentration
using near-IR radiation diffuse-reflection laser spectroscopy.
Similar near-IR spectrometric devices are also described in U.S.
Pat. No. 5,086,229 to Rosenthal et al. and U.S. Pat. No. 4,975,581
to Robinson et al.
[0008] U.S. Pat. Nos. 5,139,023 to Stanley et al., and 5,443,080 to
D'Angelo et al. describe transdermal blood glucose monitoring
devices that rely on a permeability enhancer (e.g., a bile salt) to
facilitate transdermal movement of glucose along a concentration
gradient established between interstitial fluid and a receiving
medium. U.S. Pat. No. 5,036,861 to Sembrowich describes a passive
glucose monitor that collects perspiration through a skin patch,
where a cholinergic agent is used to stimulate perspiration
secretion from the eccrine sweat gland. Similar perspiration
collection devices are described in U.S. Pat. No. 5,076,273 to
Schoendorfer and U.S. Pat. No. 5,140,985 to Schroeder.
[0009] In addition, U.S. Pat. No. 5,279,543 to Glikfeld et al.
describes the use of iontophoresis to noninvasively sample a
substance through skin into a receptacle on the skin surface.
Glikfeld teaches that this sampling procedure can be coupled with a
glucose-specific biosensor or glucose-specific electrodes in order
to monitor blood glucose. Finally, International Publication No. WO
96/00110, published Jan. 4, 1996, describes an iontophoretic
apparatus for transdermal monitoring of a target substance, wherein
an iontophoretic electrode is used to move an analyte into a
collection reservoir and a biosensor is used to detect the target
analyte present in the reservoir. Finally, International
Publication No. WO 96/00110 to Tamada describes an iontophoretic
apparatus for transdermal monitoring of a target substance, where
an iontophoretic electrode is used to move an analyte into a
collection reservoir and a biosensor is used to detect the target
analyte present in the reservoir.
SUMMARY OF THE INVENTION
[0010] The present invention relates generally to collection
assembly, laminates and autosensor assemblies for use in a sampling
device. More particularly, the present collection assembly,
laminates and autosensor assemblies are used in a transdermal
sampling device that is placed in operative contact with a skin or
mucosal surface of the biological system to obtain a chemical
signal associated with an analyte of interest. The sampling device
transdermally extracts the analyte from the biological system
using, for example, an iontophoretic sampling technique. The
transdermal sampling device can be maintained in operative contact
with the skin or mucosal surface of the biological system to
provide, for example, continual or continuous analyte
measurement.
[0011] The analyte can be any specific substance or component that
one is desirous of detecting and/or measuring in a chemical,
physical, enzymatic, or optical analysis. The analyte can be any
specific substance or component that one is desirous of detecting
and/or measuring in a chemical, physical, enzymatic, or optical
analysis. Such analytes include, but are not limited to, amino
acids, enzyme substrates or products indicating a disease state or
condition, other markers of disease states or conditions, drugs of
abuse, therapeutic and/or pharmacologic agents (e.g., theophylline,
anti-HIV drugs, lithium, anti-epileptic drugs, cyclosporin,
chemotherapeutics), electrolytes, physiological analytes of
interest (e.g., urate/uric acid, carbonate, calcium, potassium,
sodium, chloride, bicarbonate (CO.sub.2), glucose, urea (blood urea
nitrogen), lactate/lactic acid, hydroxybutyrate, cholesterol,
triglycerides, creatine, creatinine, insulin, hematocrit, and
hemoglobin), blood gases (carbon dioxide, oxygen, pH), lipids,
heavy metals (e.g., lead, copper), and the like. In preferred
embodiments, the analyte is a physiological analyte of interest,
for example glucose, or a chemical that has a physiological action,
for example a drug or pharmacological agent.
[0012] Thus, one embodiment of the invention provides a tri-layer
collection assembly for use in a transdermal sampling device. The
collection assembly is formed from a series of functional layers
including: (1) a first surface layer that is comprised of a
substantially planar material that has an opening which extends
therethrough; (2) a second surface layer that is also comprised of
a substantially planar material and has an opening therein; and (3)
an intervening layer that is positioned between the first and
second surface layers, wherein the intervening layer is comprised
of an ionically conductive material. The first and second surface
layers overlap the intervening layer at corresponding positions,
and contact each other at their corresponding overlaps, such
overlaps can be used to form a laminate structure. The openings in
the first and second surface layers are axially aligned to provide
a flow path through the laminate (i.e., a flow path that extends
between the two surfaces and passes through the intervening layer).
The overhangs provided by the mask and retaining layers are
generally contacted with each other to sandwich the collection
insert therebetween and form the assembly.
[0013] It is a related object of the invention to provide an
autosensor assembly for use in a transdermal sampling device,
wherein the assembly comprises the three functional layers of the
above-described collection assembly or laminate, an electrode
assembly, and, typically, a support tray.
[0014] It is a further object of the invention to provide a two
layer collection assembly or laminate for use in a transdermal
sampling device. The collection assembly is formed from two
functional layers including: (1) a surface layer that is comprised
of a substantially planar material that has an opening which
extends therethrough; and (2) a second layer. The second layer is
formed from the combination of a gasket and a collection insert.
The gasket is comprised of a substantially planar material having a
top face, a bottom face, and an opening extending between the top
and bottom faces. The top face of the gasket is attached to the
bottom face of the surface layer, and the opening in the gasket is
axially aligned with the opening in the surface layer to provide a
flow path through the laminate. The collection insert is arranged
within and substantially fills the opening in the gasket such that
the collection insert is aligned with the opening in the surface
layer and rests against or is otherwise attached to a portion of
the surface layer.
[0015] It is a related object of the invention to provide an
autosensor assembly for use in a transdermal sampling device,
wherein the assembly comprises the two layers of the
above-described collection assembly or laminate, an electrode
assembly with which the collection assembly is functionally
aligned, and, typically, a support tray.
[0016] Thus, in one embodiment, the invention relates to a
collection assembly for use in a iontophoretic sampling device
useful to monitor a selected analyte or derivatives thereof present
in a biological system. The collection assembly comprises:
[0017] a) a collection insert layer comprised of an ionically
conductive material having first and second portions, each portion
having first and second surfaces,
[0018] b) a mask layer comprised of a material that is
substantially impermeable to the selected analyte or derivatives
thereof, wherein the mask layer (i) has inner and outer faces and
said outer face provides contact with said biological system and
the inner face is positioned in facing relation with the first
surface of each collection insert, (ii) defines first and second
openings that are aligned with the first and second portions of the
collection insert layer, (iii) each opening exposes at least a
portion of the first surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang;
and
[0019] (c) a retaining layer having (i) inner and outer faces
wherein the inner face is positioned in facing relation with the
second surface of each collection insert, (ii) defines first and
second openings that are aligned with the first and second portions
of the collection insert layer, (iii) each opening exposes at least
a portion of the second surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang.
[0020] In certain embodiments, the collection insert layer further
comprises a gasket layer and the gasket layer is between the mask
layer and the retaining layer.
[0021] In additional embodiments, the subject invention is directed
to a laminate comprising a collection assembly, as described above,
as well as a sealed package containing the laminate.
[0022] In still another embodiment, the invention is directed to an
autosensor assembly for use in a iontophoretic sampling device
useful to monitor an analyte present in a biological system. The
autosensor assembly comprises:
[0023] (I) a collection assembly which comprises,
[0024] a) a collection insert layer comprised of an ionically
conductive material having first and second portions, each portion
having first and second surfaces,
[0025] b) a mask layer comprised of a substantially planar material
that is substantially impermeable to the selected analyte or
derivatives thereof, wherein the mask layer (i) has inner and outer
faces and the outer face provides contact with the biological
system and the inner face is positioned in facing relation with the
first surface of each collection insert, (ii) defines first and
second openings that are aligned with the first and second portions
of the collection insert layer, (iii) each opening exposes at least
a portion of the first surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang;
[0026] (c) a retaining layer having (i) inner and outer faces
wherein the inner face is positioned in facing relation with the
second surface of each collection insert, (ii) defines first and
second openings that are aligned with the first and second portions
of the collection insert layer, (iii) each opening exposes at least
a portion of the second surface of the collection insert layer, and
(iv) has a border which extends beyond the first surface of each
portion of the collection insert layer to provide an overhang;
and
[0027] (d) where the first and second openings in the mask layer
are positioned in the collection assembly such that they are
aligned with the first and second openings in the retaining layer
and thereby define a plurality of flow paths through said
collection assembly;
[0028] (II) an electrode assembly having an inner and outer face,
the inner face comprising first and second bimodal electrodes,
wherein the first and second bimodal electrodes are aligned with
the first and second openings in the retaining layer of the
collection assembly; and
[0029] (III) a support tray that contacts the outer face of the
electrode assembly.
[0030] In alternative embodiments, the autosensor assembly further
comprises a first removable liner attached to the outer face of the
retaining layer, and/or a second removable liner attached to the
outer face of the mask layer. In addition, a plowfold liner can be
used, for example, between the electrode surfaces and the
collection inserts.
[0031] In further embodiments, the invention is directed to a
sealed package containing the autosensor assembly described above.
The sealed package may also contain a hydrating insert.
[0032] In yet another embodiment, the invention is directed to a
collection assembly for use in a iontophoretic sampling device
useful to monitor a selected analyte, or derivatives thereof,
present in a biological system. The collection assembly
comprises:
[0033] a) a mask layer comprised of a substantially planar material
that is substantially impermeable to the selected analyte or
derivatives thereof, where the mask layer has inner and outer faces
and the outer face provides contact with the biological system;
[0034] b) a collection insert layer comprised of an ionically
conductive material having first and second surfaces, and
[0035] c) the mask and collection insert layers are configured such
that (i) at least a portion of the collection insert is exposed to
provide contact with the biological system, and (ii) flow of the
analyte through the first surface of the collection insert layer
from the biological system is prevented by the mask layer for any
portion of the first surface of the collection insert layer that is
in contact with the inner face of the mask layer.
[0036] In another embodiment, the invention is directed to an
autosensor assembly comprising
[0037] (a) the collection assembly above,
[0038] (b) an electrode assembly having an inner face comprising an
electrode and an outer face, where the inner face of the electrode
assembly and the collection assembly are aligned to define a
plurality of flow paths through the collection assembly, and
[0039] (c) a support tray that contacts the outer face of the
electrode assembly.
[0040] Additional objects, advantages and novel features of the
invention will be set forth in part in the description which
follows, and in part will become apparent to those skilled in the
art upon examination of the following, or may be learned by
practice of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1A depicts a top plan view of an iontophoretic
collection reservoir and electrode assembly for use in a
transdermal sampling device.
[0042] FIG. 1B depicts the side view of the iontophoretic
collection reservoir and electrode assembly shown in FIG. 1A.
[0043] FIG. 2 is a pictorial representation of an iontophoretic
sampling device which includes the iontophoretic collection
reservoir and electrode assembly of FIGS. 1A and 1B.
[0044] FIG. 3 depicts an exploded view of one embodiment of a
collection assembly and autosensor constructed according to the
present invention.
[0045] FIG. 4 depicts an exploded view of another embodiment of a
collection assembly and autosensor constructed according to the
present invention.
[0046] FIG. 5 depicts an exploded view of a still further
embodiment of a collection assembly and autosensor constructed
according to the present invention.
[0047] FIG. 6 is a representation of one embodiment of a bimodal
electrode design. The figure presents an overhead and schematic
view of the electrode assembly 633. In the figure, the bimodal
electrode is shown at 630 and can be, for example, a Ag/AgCl
iontophoretic/counter electrode. The sensing or working electrode
(made from, for example, platinum) is shown at 631. The reference
electrode is shown at 632 and can be, for example, a Ag/AgCl
electrode. The components are mounted on a suitable nonconductive
substrate 634, for example, plastic or ceramic. The conductive
leads 637 leading to the connection pad 635 are covered by a second
nonconductive piece 636 of similar or different material. In this
example of such an electrode the working electrode area is
approximately 1.35 cm.sup.2. The dashed line in FIG. 6 represents
the plane of the cross-sectional schematic view presented in FIG.
7.
[0048] FIG. 7 is a representation of a cross-sectional schematic
view of the bimodal electrodes as they may be used in conjunction
with a reference electrode and a hydrogel pad. In the figure, the
components are as follows: bimodal electrodes 740 and 741; sensing
electrodes 742 and 743; reference electrodes 744 and 745; a
substrate 746; and hydrogel pads 747 and 748.
[0049] FIGS. 8A through 8H show general schematic diagrams for the
components of one embodiment of an autosensor of the present
invention. The general shape and dimensions of the tray are
indicated in FIG. 8A. General shape and dimensions of the electrode
assembly are indicated in FIG. 8B. A tri-layer laminate including a
mask layer, having the general shape and dimensions shown in FIG.
8C, collection inserts, having the general shape and dimensions
shown in FIG. 8D, and a retaining layer, having the general shape
and dimensions shown in FIG. 8E. Further, FIG. 8F shows the general
shape and dimensions of the liner for contacting the mask and
collection inserts (i.e., a "patient liner"). FIG. 8G shows the
general shape and dimensions of the second liner (i.e., a
"plow-fold" liner), for contacting the retaining layer and
collection inserts. FIG. 8H shows a composite figure of autosensor
components in their proper order of stacking/assembly.
[0050] FIGS. 9A through 9G show general schematic diagrams for the
components of another embodiment of an autosensor of the present
invention. The general shape and dimensions of the tray are
indicated in FIG. 9A. General shape and dimensions of the electrode
assembly are indicated in FIG. 9B. A mask layer is shown, having
the general shape and dimensions shown in FIG. 9C. The general
shape and dimensions of collection inserts are shown in FIG. 9D.
FIG. 9E shows the general shape and dimensions of the second liner
(i.e., a "plow-fold" liner), for contacting the gel retaining layer
and the collection inserts, typically eliminating contact between
the collection inserts and the iontophoretic/counter electrodes and
reference electrode prior to removal. Further, FIG. 9F shows the
general shape and dimensions of the liner for contacting the mask
layer and collection inserts (i.e., a "patient liner"). FIG. 9G
shows a composite figure of autosensor components in their proper
order of stacking/assembly.
DETAILED DESCRIPTION OF THE INVENTION
[0051] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
compositions or biological systems as such may, of course, vary. It
is also to be understood that the terminology used herein is for
the purpose of describing particular embodiments only, and is not
intended to be limiting.
[0052] It must be noted that, as used in this specification and the
appended claims, the singular forms "a", "an" and "the" include
plural referents unless the content clearly dictates otherwise.
Thus, for example, reference to "a collection insert" includes two
or more such inserts, reference to "an analyte" includes a mixture
of two or more such analytes, reference to "an electrochemically
active species" includes two or more such species, and the
like.
[0053] All publications, patents and patent applications cited
herein, whether supra or infra, are hereby incorporated by
reference in their entirety.
[0054] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention pertains. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice of the present invention, the
preferred materials and methods are described herein.
[0055] In describing and claiming the present invention, the
following terminology will be used in accordance with the
definitions set out below.
1. DEFINITIONS
[0056] The terms "analyte" and "target analyte" are used herein to
denote any physiological analyte of interest that is a specific
substance or component that is being detected and/or measured in a
chemical, physical, enzymatic, or optical analysis. A detectable
signal (e.g., a chemical signal or electrochemical signal) can be
obtained, either directly or indirectly, from such an analyte or
derivatives thereof. Furthermore, the terms "analyte" and
"substance" are used interchangeably herein, and are intended to
have the same meaning, and thus encompass any substance of
interest. In preferred embodiments, the analyte is a physiological
analyte of interest, for example, glucose, or a chemical that has a
physiological action, for example, a drug or pharmacological
agent.
[0057] A "sampling device" or "sampling system" refers to any
device for obtaining a sample from a biological system for the
purpose of determining the concentration of an analyte of interest.
As used herein, the term "sampling" means invasive, minimally
invasive or noninvasive extraction of a substance from the
biological system, generally across a membrane such as skin or
mucosa. The membrane can be natural or artificial, and can be of
plant or animal nature, such as natural or artificial skin, blood
vessel tissue, intestinal tissue, and the like. Typically, the
sampling means are in operative contact with a "reservoir," or
"collection reservoir," wherein the sampling means is used for
extracting the analyte from the biological system into the
reservoir to obtain the analyte in the reservoir. A "biological
system" includes both living and artificially maintained systems.
Examples of minimally invasive and noninvasive sampling techniques
include iontophoresis, sonophoresis, suction, electroporation,
thermal poration, passive diffusion, microfine (miniature) lances
or cannulas, subcutaneous implants or insertions, and laser
devices. Sonophoresis uses ultrasound to increase the permeability
of the skin (see, e.g., Menon et al. (1994) Skin Pharmacology
7:130-139). Suitable sonophoresis sampling systems are described in
International Publication No. WO 91/12772, published Sep. 5, 1991.
Passive diffusion sampling devices are described, for example, in
International Publication Nos.: WO 97/38126 (published Oct. 16,
1997); WO 97/42888, WO 97/42886, WO 97/42885, and WO 97/42882 (all
published Nov. 20, 1997); and WO 97/43962 (published Nov. 27,
1997). Laser devices use a small laser beam to burn a hole through
the upper layer of the patient's skin (see, e.g., Jacques et al.
(1978) J. Invest. Dermatology 88:88-93). Examples of invasive
sampling techniques include traditional needle and syringe or
vacuum sample tube devices.
[0058] A "housing" for the sampling system can further include
suitable electronics (e.g., microprocessor, memory, display and
other circuit components) and power sources for operating the
sampling system in an automatic fashion.
[0059] A "monitoring system," as used herein, refers to a system
useful for continually or continuously measuring a physiological
analyte present in a biological system. Such a system typically
includes, but is not limited to, sampling means, sensing means, and
a microprocessor means in operative communication with the sampling
means and the sensing means.
[0060] The term "artificial," as used herein, refers to an
aggregation of cells of monolayer thickness or greater which are
grown or cultured in vivo or in vitro, and which function as a
tissue of an organism but are not actually derived, or excised,
from a pre-existing source or host.
[0061] The term "subject" encompasses any warm-blooded animal,
particularly including a member of the class Mammalia such as,
without limitation, humans and nonhuman primates such as
chimpanzees and other apes and monkey species; farm animals such as
cattle, sheep, pigs, goats and horses; domestic mammals such as
dogs and cats; laboratory animals including rodents such as mice,
rats and guinea pigs, and the like. The term does not denote a
particular age or sex. Thus, adult and newborn subjects, as well as
fetuses, whether male or female, are intended to be covered.
[0062] As used herein, the term "continual measurement" intends a
series of two or more measurements obtained from a particular
biological system, which measurements are obtained using a single
device maintained in operative contact with the biological system
over the time period in which the series of measurements is
obtained. The term thus includes continuous measurements.
[0063] The term "transdermal," as used herein, includes both
transdermal and transmucosal techniques, i.e., extraction of a
target analyte across skin or mucosal tissue. Aspects of the
invention which are described herein in the context of
"transdermal," unless otherwise specified, are meant to apply to
both transdermal and transmucosal techniques.
[0064] The term "transdermal extraction," or "transdermally
extracted" intends any noninvasive, or at least minimally invasive
sampling method, which entails extracting and/or transporting an
analyte from beneath a tissue surface across skin or mucosal
tissue. The term thus includes extraction of an analyte using
iontophoresis (reverse iontophoresis), electroosmosis,
sonophoresis, microdialysis, suction, and passive diffusion. These
methods can, of course, be coupled with application of skin
penetration enhancers or skin permeability enhancing technique such
as tape stripping or pricking with micro-needles. The term
"transdermally extracted" also encompasses extraction techniques
which employ thermal poration, electroporation, microfine lances,
microfine canulas, subcutaneous implants or insertions, and the
like.
[0065] The term "iontophoresis" intends a method for transporting
substances across tissue by way of an application of electrical
energy to the tissue. In conventional iontophoresis, a reservoir is
provided at the tissue surface to serve as a container of material
to be transported. Iontophoresis can be carried out using standard
methods known to those of skill in the art, for example, by
establishing an electrical potential using a direct current (DC)
between fixed anode and cathode "iontophoretic electrodes,"
alternating a direct current between anode and cathode
iontophoretic electrodes, or using a more complex waveform such as
applying a current with alternating polarity (AP) between
iontophoretic electrodes (so that each electrode is alternately an
anode or a cathode).
[0066] The term "reverse iontophoresis" refers to the movement of a
substance from a biological fluid across a membrane by way of an
applied electric potential or current. In reverse iontophoresis, a
reservoir is provided at the tissue surface to receive the
extracted material.
[0067] "Electroosmosis" refers to the movement of a substance
through a membrane by way of an electric field-induced convective
flow. The terms iontophoresis, reverse iontophoresis, and
electroosmosis, will be used interchangeably herein to refer to
movement of any ionically charged or uncharged substance across a
membrane (e.g., an epithelial membrane) upon application of an
electric potential to the membrane through an ionically conductive
medium.
[0068] The term "sensing device," "sensing means," or "biosensor
device" encompasses any device that can be used to measure the
concentration of an analyte, or derivative thereof, of interest.
Preferred sensing devices for detecting blood analytes generally
include electrochemical devices and chemical devices. Examples of
electrochemical devices include the Clark electrode system (see,
e.g., Updike, et al., (1967) Nature 214:986-988), and other
amperometric, coulometric, or potentiometric electrochemical
devices. Examples of chemical devices include conventional
enzyme-based reactions as used in the Lifescan.RTM. glucose monitor
(Johnson and Johnson, New Brunswick, N.J.) (see, e.g., U.S. Pat.
No. 4,935,346 to Phillips, et al.).
[0069] A "biosensor" or "biosensor device" includes, but is not
limited to, a "sensor element" which includes, but is not limited
to, a "biosensor electrode" or "sensing electrode" or "working
electrode" which refers to the electrode that is monitored to
determine the amount of electrical signal at a point in time or
over a given time period, which signal is then correlated with the
concentration of a chemical compound. The sensing electrode
comprises a reactive surface which converts the analyte, or a
derivative thereof, to electrical signal. The reactive surface can
be comprised of any electrically conductive material such as, but
not limited to, platinum-group metals (including, platinum,
palladium, rhodium, ruthenium, osmium, and iridium), nickel,
copper, silver, and carbon, as well as, oxides, dioxides,
combinations or alloys thereof. Some catalytic materials,
membranes, and fabrication technologies suitable for the
construction of amperometric biosensors were described by Newman,
J. D., et al.(Analytical Chemistry 67(24), 4594-4599, 1995).
[0070] The "sensor element" can include components in addition to a
biosensor electrode, for example, it can include a "reference
electrode," and a "counter electrode." The term "reference
electrode" is used herein to mean an electrode that provides a
reference potential, e.g., a potential can be established between a
reference electrode and a working electrode. The term "counter
electrode" is used herein to mean an electrode in an
electrochemical circuit which acts as a current source or sink to
complete the electrochemical circuit. Although it is not essential
that a counter electrode be employed where a reference electrode is
included in the circuit and the electrode is capable of performing
the function of a counter electrode, it is preferred to have
separate counter and reference electrodes because the reference
potential provided by the reference electrode is most stable when
it is at equilibrium. If the reference electrode is required to act
further as a counter electrode, the current flowing through the
reference electrode may disturb this equilibrium. Consequently,
separate electrodes functioning as counter and reference electrodes
are most preferred.
[0071] In one embodiment, the "counter electrode" of the "sensor
element" comprises a "bimodal electrode." The term "bimodal
electrode" as used herein typically refers to an electrode which is
capable of functioning non-simultaneously as, for example, both the
counter electrode (of the "sensor element") and the iontophoretic
electrode (of the "sampling means").
[0072] The terms "reactive surface," and "reactive face" are used
interchangeably herein to mean the surface of the sensing electrode
that: (1) is in contact with the surface of an electrolyte
containing material (e.g. gel) which contains an analyte or through
which an analyte, or a derivative thereof, flows from a source
thereof; (2) is comprised of a catalytic material (e.g., carbon,
platinum, palladium, rhodium, ruthenium, or nickel and/or oxides,
dioxides and combinations or alloys thereof) or a material that
provides sites for electrochemical reaction; (3) converts a
chemical signal (e.g. hydrogen peroxide) into an electrical signal
(e.g., an electrical current); and (4) defines the electrode
surface area that, when composed of a reactive material, is
sufficient to drive the electrochemical reaction at a rate
sufficient to generate a detectable, reproducibly measurable,
electrical signal that is correlatable with the amount of analyte
present in the electrolyte.
[0073] The term "collection reservoir" is used to describe any
suitable containment means for containing a sample extracted from a
biological system. For example, the collection reservoir can be a
receptacle containing a material which is ionically conductive
(e.g., water with ions therein), or alternatively, it can be a
material, such as, a sponge-like material or hydrophilic polymer,
used to keep the water in place. Such collection reservoirs can be
in the form of a hydrogel (for example, in the form of a disk or
pad). Hydrogels are typically referred to as "collection inserts."
Other suitable collection reservoirs include, but are not limited
to, tubes, vials, capillary collection devices, cannulas, and
miniaturized etched, ablated or molded flow paths.
[0074] An "tonically conductive material" refers to any material
that provides ionic conductivity, and through which
electrochemically active species can diffuse. The ionically
conductive material can be, for example, a solid, liquid, or
semi-solid (e.g., in the form of a gel) material that contains an
electrolyte, which can be composed primarily of water and ions
(e.g., sodium chloride), and generally comprises 50% or more water
by weight. The material can be in the form of a gel, a sponge or
pad (e.g., soaked with an electrolytic solution), or any other
material that can contain an electrolyte and allow passage
therethrough of electrochemically active species, especially the
analyte of interest.
[0075] The term "physiological effect" encompasses effects produced
in the subject that achieve the intended purpose of a therapy. In
preferred embodiments, a physiological effect means that the
symptoms of the subject being treated are prevented or alleviated.
For example, a physiological effect would be one that results in
the prolongation of survival in a patient.
[0076] A "laminate", as used herein, refers to structures comprised
of at least two bonded layers. The layers may be bonded by welding
or through the use of adhesives. Examples of welding include, but
are not limited to, the following: ultrasonic welding, heat
bonding, and inductively coupled localized heating followed by
localized flow. Examples of common adhesives include, but are not
limited to, pressure sensitive adhesives, thermoset adhesives,
cyanocrylate adhesives, epoxies, contact adhesives, and heat
sensitive adhesives. An example of a laminate of the present
invention is a mask layer, collection inserts, and a retaining
layer (e.g., FIG. 3, 50) where at least the mask and retaining
layer are bonded to each other.
[0077] A "collection assembly", as used herein, refers to
structures comprised of several layers, where the assembly includes
at least one collection insert, for example a hydrogel. An example
of a collection assembly of the present invention is a mask layer,
collection inserts, and a retaining layer (e.g., FIG. 3, 50) where
the layers are held in appropriate, functional relationship to each
other but are not necessarily a laminate, i.e., the layers may not
be bonded together. The layers may, for example, be held together
by interlocking geometry or friction.
[0078] An "autosensor assembly", as used herein, refers to
structures generally comprising a mask layer, collection inserts, a
retaining layer, an electrode assembly, and a support tray. The
autosensor assembly may also include liners (e.g., the autosensor
assembly shown in FIG. 3) where the layers are held in appropriate,
functional relationship to each other.
[0079] The mask and retaining layers are preferably composed of
materials that are substantially impermeable to the analyte
(chemical signal) to be detected (e.g., glucose); however, the
material can be permeable to other substances. By "substantially
impermeable" is meant that the material reduces or eliminates
chemical signal transport (e.g., by diffusion). The material can
allow for a low level of chemical signal transport, with the
proviso that chemical signal that passes through the material does
not cause significant edge effects at the sensing electrode.
[0080] "Substantially planar" as used herein, includes a slightly
curved surface that conforms, for example, to the curvature of the
forearm or upper arm of a subject. A "substantially planar" surface
is, for example, a surface having a shape to which skin can
conform, i.e., creating contact between the skin and the surface. A
further example includes shapes that have large length and width
relative to their depth (e.g., 10:1 or greater) and permit the skin
to conform to their surface topography.
[0081] By the term "printed" as used herein is meant a
substantially uniform deposition of an electrode formulation onto
one surface of a substrate (i.e., the base support). It will be
appreciated by those skilled in the art that a variety of
techniques may be used to effect substantially uniform deposition
of a material onto a substrate, e.g., Gravure-type printing,
extrusion coating, screen coating, spraying, painting, or the
like.
2. EXEMPLARY EMBODIMENTS OF SAMPLING SYSTEMS
[0082] The present invention relates to laminates, collection
assemblies, and other components useful in a sampling device for
transdermally extracting and measuring the concentration of a
target analyte present in a biological system. Such sampling
devices are generally used for extracting small amounts of a target
analyte from the biological system, and then sensing and/or
quantifying the concentration of the target analyte. Measurement
and/or sampling with the sampling device can be carried out in a
continual or continuous manner. Continual or continuous
measurements allow for closer monitoring of target analyte
concentration fluctuations. In general, the sampling device
comprises a biosensor with an electrochemical sensing element, and
the sampling device is preferably used to perform continual
transdermal or transmucosal sampling of blood glucose.
[0083] The analyte can be any specific substance or component that
one is desirous of detecting and/or measuring in a chemical,
physical, enzymatic, or optical analysis. Such analytes include,
but are not limited to, amino acids, enzyme substrates or products
indicating a disease state or condition, other markers of disease
states or conditions, drugs of abuse, therapeutic and/or
pharmacologic agents (e.g., theophylline, anti-HIV drugs, lithium,
anti-epileptic drugs, cyclosporin, chemotherapeutics),
electrolytes, physiological analytes of interest (e.g., urate/uric
acid, carbonate, calcium, potassium, sodium, chloride, bicarbonate
(CO.sub.2), glucose, urea (blood urea nitrogen), lactate/lactic
acid, hydroxybutyrate, cholesterol, triglycerides, creatine,
creatinine, insulin, hematocrit, and hemoglobin), blood gases
(carbon dioxide, oxygen, pH), lipids, heavy metals (e.g., lead,
copper), and the like. In preferred embodiments, the analyte is a
physiological analyte of interest, for example glucose, or a
chemical that has a physiological action, for example a drug or
pharmacological agent.
[0084] In order to facilitate detection of the analyte, an enzyme
can be disposed in the collection reservoir, or, if several
collection reservoirs are used, the enzyme can be disposed in
several or all of the reservoirs. The selected enzyme is capable of
catalyzing a reaction with the extracted analyte (in this case
glucose) to the extent that a product of this reaction can be
sensed, e.g., can be detected electrochemically from the generation
of a current which current is detectable and proportional to the
concentration or amount of the analyte which is reacted. A suitable
enzyme is glucose oxidase which oxidizes glucose to gluconic acid
and hydrogen peroxide. The subsequent detection of hydrogen
peroxide on an appropriate biosensor electrode generates two
electrons per hydrogen peroxide molecule which create a current
which can be detected and related to the amount of glucose entering
the device. Glucose oxidase (GOx) is readily available commercially
and has well known catalytic characteristics. However, other
enzymes can also be used, so long as they specifically catalyze a
reaction with an analyte or substance of interest to generate a
detectable product in proportion to the amount of analyte so
reacted.
[0085] In like manner, a number of other analyte-specific enzyme
systems can be used in the invention, which enzyme systems operate
on much the same general techniques. For example, a biosensor
electrode that detects hydrogen peroxide can be used to detect
ethanol using an alcohol oxidase enzyme system, or similarly uric
acid with urate oxidase system, urea with a urease system,
cholesterol with a cholesterol oxidase system, and theophylline
with a xanthine oxidase system.
[0086] In addition, the oxidase enzyme (used for hydrogen
peroxide-based detection) can be replaced with another redox
system, for example, the dehydrogenase-enzyme NAD-NADH, which
offers a separate route to detecting additional analytes.
Dehydrogenase-based sensors can use working electrodes made of gold
or carbon (via mediated chemistry). Examples of analytes suitable
for this type of monitoring include, but are not limited to,
cholesterol, ethanol, hydroxybutyrate, phenylalanine,
triglycerides, and urea. Further, the enzyme can be eliminated and
detection can rely on direct electrochemical or potentiometric
detection of an analyte. Such analytes include, without limitation,
heavy metals (e.g., cobalt, iron, lead, nickel, zinc), oxygen,
carbonate/carbon dioxide, chloride, fluoride, lithium, pH,
potassium, sodium, and urea. Also, the sampling system described
herein can be used for therapeutic drug monitoring, for example,
monitoring anti-epileptic drugs (e.g., phenytion), chemotherapy
(e.g., adriamycin), hyperactivity (e.g., ritalin), and
anti-organ-rejection (e.g., cyclosporin).
[0087] More specifically, a non-invasive glucose monitoring
(sampling) device is used to measure changes in glucose levels in
an animal subject over a wide range of glucose concentrations. The
sampling method is based on transdermal glucose extraction, and the
sensing method is based on electrochemical detection technology.
The device can be contacted with the biological system
continuously, and automatically obtains glucose samples in order to
measure glucose concentration at various selected intervals.
[0088] Sampling is carried out continually by noninvasively
extracting glucose through the skin of the patient. More
particularly, an iontophoretic current is applied to a surface of
the skin of a subject. When the current is applied, ions or charged
molecules pull along other uncharged molecules or particles such as
glucose which are drawn into a collection insert placed on the
surface of the skin. The collection insert may comprise any
ionically conductive material and is preferably in the form of a
hydrogel which is comprised of a hydrophilic material, water and an
electrolyte.
[0089] The collection insert may further contain an enzyme which
catalyzes a reaction of glucose to form an easily detectable
species. The enzyme is preferably glucose oxidase (GOx) which
catalyzes the reaction between glucose and oxygen and results in
the production of hydrogen peroxide. The hydrogen peroxide reacts
at a catalytic surface of a biosensor electrode, resulting in the
generation of electrons which create a detectable biosensor current
(raw signal). Based on the amount of biosensor current created over
a given period of time, a measurement is taken, which measurement
is related to the amount of glucose drawn into the collection
insert over a given period of time.
[0090] When the reaction is complete, the process can be repeated
and a subsequent measurement obtained. More specifically, the
iontophoretic current is again applied, glucose is drawn through
the skin surface into the collection insert, and the reaction is
catalyzed in order to create a biosensor current. These sampling
(extraction) and sensing operations can be integrated such that
glucose is extracted into a hydrogel collection pad where it
contacts the GOx enzyme. The GOx enzyme converts glucose and oxygen
in the hydrogel to hydrogen peroxide which diffuses to the sensor
and is catalyzed by the sensor to regenerate oxygen and form
electrons. The electrons generate an electrical signal that can be
measured, analyzed, and correlated to blood glucose.
[0091] In one embodiment of the present invention, the sampling
system can have two collection reservoirs which contain, for
example, an active collection reservoir, having the GOx enzyme, and
a blank collection reservoir (without the GOx enzyme); or, in an
alternative, two active reservoirs, i.e., two reservoirs containing
the GOx enzyme. In the case of an active collection reservoir and a
blank collection reservoir signal can be adjusted by subtraction of
the blank reservoir signal from the signal obtained from the active
reservoir. In the case of two active collection reservoirs the
signals can be summed and averaged, or a total of the two signals
can be used. This signal, for example the detected current, is then
used alone or in combination with other factors (for example,
glucose concentration at a calibration point, skin temperature,
conductivity, voltage, time since calibration of the system, etc.)
to provide a glucose concentration value.
[0092] In particular embodiments, the detected current can be
correlated with the subject's blood glucose concentration
(typically using statistical algorithms associated with a
microprocessor) so that the system controller may display the
subject's actual blood glucose concentration as measured by the
sampling system. For example, the system can be calibrated to the
subject's actual blood glucose concentration by sampling the
subject's blood during a standard glucose tolerance test, and
analyzing the blood glucose using both a standard blood glucose
monitor and the sampling system of the present invention. In
addition or alternately, the sampling system can be calibrated at a
calibration time point where the signal obtained from the sampling
system at that time point is correlated to blood glucose
concentration at that time point as determined by direct blood
testing (for example, glucose concentration can be determined using
a HemoCue.RTM. clinical analyzer (HemoCue AB, Sweden)). In this
manner, measurements obtained by the sampling system can be
correlated to actual values using known statistical techniques.
Such statistical techniques can be formulated as algorithm(s) and
incorporated in a microprocessor associated with the sampling
system.
[0093] A generalized method for continual monitoring of a
physiological analyte is disclosed in International Publication No.
WO 97/24059, published Jul. 10, 1997, which publication is
incorporated herein by reference. As noted in that publication, the
analyte is extracted into a reservoir containing a hydrogel which
is preferably comprised of a hydrophilic material of the type
described in International Publication No. WO 97/02811, published
Jan. 30, 1997, which publication is incorporated herein by
reference. Suitable hydrogel materials include, but are not limited
to, polyethylene oxide, polyacrylic acid, polyvinylalcohol and
related hydrophilic polymeric materials combined with water to form
an aqueous gel.
[0094] In the above non-invasive glucose monitoring device, a
biosensor electrode is positioned against a surface of the hydrogel
opposite the surface of the hydrogel which contacts the skin. The
sensor electrode acts as a detector which detects current generated
by hydrogen peroxide in the redox reaction, or more specifically
detects current which is generated by the electrons generated by
the redox reaction catalyzed by the reactive surface of the
electrode (International Publication No. WO 96/00110, published
Jan. 4, 1996, and International Publication No. WO 97/10499,
published Mar. 2, 1997, which publications are also incorporated
herein by reference).
[0095] Referring now to FIGS. 1A and 1B, an exemplary iontophoretic
collection reservoir and electrode assembly for use in a
transdermal sensing device is generally indicated at 2. The
assembly comprises two iontophoretic collection reservoirs, 4 and
6, each generally comprising a conductive medium 8, and 10
(preferably cylindrical hydrogel pads), respectively disposed
therein. First (12) and second (14) ring-shaped iontophoretic
electrodes are respectively contacted with conductive medium 8 and
10. The first iontophoretic electrode 12 surrounds three biosensor
electrodes which are also contacted with the conductive medium 8, a
working electrode 16, a reference electrode 18, and a counter
electrode 20. A guard ring 22 separates the biosensor electrodes
from the iontophoretic electrode 12 to minimize noise from the
iontophoretic circuit. Conductive contacts provide communication
between the electrodes and an associated power source and control
means as described below. A similar biosensor electrode arrangement
can be contacted with the conductive medium 10, or the medium may
not have a sensor means contacted therewith (e.g., in order to
provide a blank).
[0096] Referring now to FIG. 2, the iontophoretic collection
reservoir and electrode assembly 2 of FIGS. 1A and 1B is shown in
exploded view in combination with a suitable iontophoretic sampling
device housing 32. The housing can be a plastic case or other
suitable structure which preferably is configured to be worn on a
subject's arm in a manner similar to a wrist watch. As can be seen,
conductive media 8 and 10 (hydrogel pads) are separable from the
assembly 2; however, when the assembly 2 and the housing 32 are
combined to provide an operational iontophoretic sampling device
30, the media are in contact with the electrodes to provide a
electrical contact therewith.
[0097] A power source (e.g., one or more rechargeable or
nonrechargeable batteries) can be disposed within the housing 32 or
within the straps 34 which hold the device in contact with a skin
or mucosal surface of a subject. In use, an electric potential
(either direct current or a more complex waveform) is applied
between the two iontophoretic electrodes 12 and 14 such that
current flows from the first iontophoretic electrode 12, through
the first conductive medium 8 into the skin or mucosal surface, and
then back out through the second conductive medium 10 to the second
iontophoretic electrode 14. The current flow is sufficient to
extract substances including an analyte of interest through the
skin into one or both of collection reservoirs 4 and 6. The
electric potential may be applied using any suitable technique, for
example, the applied current density may be in the range of about
0.01 to 0.5 mA/cm.sup.2. In a preferred embodiment, the device is
used for continual or continuous monitoring, and the polarity of
iontophoretic electrodes 12 and 14 is alternated at a rate of about
one switch every 10 seconds to about one switch every hour so that
each electrode is alternately a cathode or an anode. After a
suitable iontophoretic extraction period, one or both of the sensor
electrode sets can be activated in order to detect extracted
substances including the analyte of interest. Operation of the
iontophoretic sampling device 30 is preferably controlled by a
controller 36 (e.g., a microprocessor), which interfaces with the
iontophoretic electrodes, the sensor electrodes, the power supply,
as well as optional temperature and/or conductance sensing
elements, a display, and other electronics. For example, the
controller 36 can include a programmable controlled circuit
source/sink drive for driving the iontophoretic electrodes. Power
and reference voltage are provided to the sensor electrodes, and
signal amplifiers can be used to process the signal from the
working electrode or electrodes. In general, the controller
discontinues the iontophoretic current drive during sensing
periods.
[0098] In a further aspect of the above embodiments, the sensor
element can also include a reference electrode, and a counter
electrode. Further, a counter electrode of the sensor element and
an iontophoretic electrode of the sampling system can be combined
as a single bimodal electrode where the electrode is not used
simultaneously for both functions, i.e., where the counter and
iontophoretic functions are separately carried out at different
times.
[0099] In one aspect, the sampling device can operate in an
alternating polarity mode, for example, using first and second
bimodal electrodes (FIG. 7, 740 and 741) and two collection
reservoirs (FIG. 7, 747 and 748). Each bi-modal electrode (FIG. 6,
630; FIG. 7, 740 and 741) serves two functions depending on the
phase of the operation: (1) an electro-osmotic electrode (or
iontophoretic electrode) used to electrically draw analyte from a
source into a collection reservoir comprising water and an
electrolyte, and to the area of the electrode subassembly; and (2)
as a counter electrode to the first sensing electrode at which the
chemical compound is catalytically converted at the face of the
sensing electrode to produce an electrical signal.
[0100] The reference (FIG. 7, 744 and 745; FIG. 6, 632) and sensing
electrodes (FIG. 7, 742 and 743; FIG. 6, 631), as well as, the
bimodal electrode (FIG. 7, 740 and 741; FIG. 6, 630) are connected
to a standard potentiostat circuit during sensing. In general,
practical limitations of the system require that the bimodal
electrode will not act as both a counter and iontophoretic
electrode simultaneously.
[0101] The general operation of an iontophoretic sampling system is
the cyclical repetition of two phases: (1) a reverse-iontophoretic
phase, followed by a (2) sensing phase. During the reverse
iontophoretic phase, the first bimodal electrode (FIG. 7, 740) acts
as an iontophoretic cathode and the second bimodal electrode (FIG.
7, 741) acts as an iontophoretic anode to complete the circuit.
Analyte is collected in the reservoirs, for example, a hydrogel
(FIG. 7, 747 and 748). At the end of the reverse iontophoretic
phase, the iontophoretic current is turned off. During the sensing
phase, in the case of glucose, a potential is applied between the
reference electrode (FIG. 7, 744) and the sensing electrode (FIG.
7, 742). The chemical signal reacts catalytically on the catalytic
face of the first sensing electrode (FIG. 7, 742) producing an
electrical current, while the first bi-modal electrode (FIG. 7,
740) acts as a counter electrode to complete the electrical
circuit.
[0102] The electrode described is particularly adapted for use in
conjunction with a hydrogel collection reservoir system for
monitoring glucose levels in a subject through the reaction of
collected glucose with the enzyme glucose oxidase present in the
hydrogel matrix.
[0103] The bi-modal electrode is preferably comprised of Ag/AgCl;
other suitable substances are can be determined in view of the
teachings of the present disclosure and the prior art. The
electrochemical reaction which occurs at the surface of this
electrode serves as a facile source or sink for electrical current.
This property is especially important for the iontophoresis
function of the electrode. Lacking this reaction, the iontophoresis
current could cause the hydrolysis of water to occur at the
iontophoresis electrodes causing pH changes and possible gas bubble
formation. The pH changes to acidic or basic pH could cause skin
irritation or burns. The ability of an Ag/AgCl electrode to easily
act as a source of sink current is also an advantage for its
counter electrode function. For a three electrode electrochemical
cell to function properly, the current generation capacity of the
counter electrode should not limit the speed of the reaction at the
sensing electrode. In the case of a large sensing electrode, the
counter electrode should be able to source proportionately larger
currents.
[0104] The design of the sampling system provides for a larger
sensing electrode (see for example, FIG. 6) than previously
designed. Consequently, the size of the bimodal electrode should be
sufficient so that when acting as a counter electrode with respect
to the sensing electrode the counter electrode does not become
limiting the rate of catalytic reaction at the sensing electrode
catalytic surface.
[0105] Two methods exist to ensure that the counter electrode does
not limit the current at the sensing electrode: (1) the bi-modal
electrode is made much larger than the sensing electrode, or (2) a
facile counter reaction is provided.
[0106] During the reverse iontophoretic phase, the power source
provides a current flow to the first bi-modal electrode to
facilitate the extraction of the chemical signal into the
reservoir. During the sensing phase, the power source is used to
provide voltage to the first sensing electrode to drive the
conversion of chemical signal retained in reservoir to electrical
signal at the catalytic face of the sensing electrode. The power
source also maintains a fixed potential at the electrode where, for
example, hydrogen peroxide is converted to molecular oxygen,
hydrogen ions, and electrons, which is compared with the potential
of the reference electrode during the sensing phase. While one
sensing electrode is operating in the sensing mode it is
electrically connected to the adjacent bimodal electrode which acts
as a counter electrode at which electrons generated at the sensing
electrode are consumed.
[0107] The electrode sub-assembly can be operated by electrically
connecting the bimodal electrodes such that each electrode is
capable of functioning as both an iontophoretic electrode and
counter electrode along with appropriate sensing electrode(s) and
reference electrode(s), to create standard potentiostat
circuitry.
[0108] A potentiostat is an electrical circuit used in
electrochemical measurements in three electrode electrochemical
cells. A potential is applied between the reference electrode and
the sensing electrode. The current generated at the sensing
electrode flows through circuitry to the counter electrode (i.e.,
no current flows through the reference electrode to alter its
equilibrium potential). Two independent potentiostat circuits can
be used to operate the two biosensors. For the purpose of the
present sampling system, the electrical current measured at the
sensing electrode subassembly is the current that is correlated
with an amount of chemical signal.
[0109] With regard to continual operation for extended periods of
time, Ag/AgCl electrodes are provided herein which are capable of
repeatedly forming a reversible couple which operates without
unwanted electrochemical side reactions (which could give rise to
changes in pH, and liberation of hydrogen and oxygen due to water
hydrolysis). The Ag/AgCl electrodes of the present sampling system
are thus formulated to withstand repeated cycles of current passage
in the range of about 0.01 to 1.0 mA per cm.sup.2 of electrode
area. With regard to high electrochemical purity, the Ag/AgCl
components are dispersed within a suitable polymer binder. One such
example of a suitable binder is styrene acrylonitrile (SAN) to
provide an electrode composition which is not susceptible to attack
(e.g., plasticization) by components in the collection reservoir,
e.g., the hydrogel composition. The electrode compositions are also
formulated using analytical- or electronic-grade reagents and
solvents, and the polymer binder composition is selected to be free
of electrochemically active contaminants which could diffuse to the
biosensor to produce a background current.
[0110] Since the Ag/AgCl iontophoretic electrodes must be capable
of continual cycling over extended periods of time, the absolute
amounts of Ag and AgCl available in the electrodes, and the overall
Ag/AgCl availability ratio, can be adjusted to provide for the
passage of high amounts of charge. Although not limiting in the
sampling system described herein, the Ag/AgCl ratio can approach
unity. In order to operate within the preferred system which uses a
biosensor having a geometric area of 0.1 to 3 cm.sup.2, the
iontophoretic electrodes are configured to provide an approximate
electrode area of 0.3 to 1.0 cm.sup.2, preferably about 0.85
cm.sup.2. These electrodes provide for reproducible, repeated
cycles of charge passage at current densities ranging from about
0.01 to 1.0 mA/cm.sup.2 of electrode area. More particularly,
electrodes constructed according to the above formulation
parameters, and having an approximate electrode area of 0.85
cm.sup.2, are capable of a reproducible total charge passage (in
both anodic and cathodic directions) of 270 mC, at a current of
about 0.3 mA (current density of 0.35 mA/cm.sup.2) for 48 cycles in
a 24 hour period.
[0111] Once formulated, the Ag/AgCl electrode composition is
affixed to a suitable rigid or flexible nonconductive surface (for
example, polyester, polycarbonate, vinyl, acrylic, PETG
(polyethylene terephthalate copolymer), PEN, and polyimide) as
described above with respect to the biosensor electrode
composition. A silver (Ag) underlayer is first applied to the
surface in order to provide uniform conduction. The Ag/AgCl
electrode composition is then applied over the Ag underlayer in any
suitable pattern or geometry using various thin film techniques,
such as sputtering, evaporation, vapor phase deposition, or the
like, or using various thick film techniques, such as film
laminating, electroplating, or the like. Alternatively, the Ag/AgCl
composition can be applied using screen printing, pad printing,
inkjet methods, transfer roll printing, or similar techniques.
Preferably, both the Ag underlayer and the Ag/AgCl electrode are
applied using a low temperature screen print onto a polymeric
substrate, for example, polyester. This low temperature screen
print can be carried out at about 125 to 160.degree. C., and the
screening can be carried out using a suitable mesh, ranging from
about 100-400 mesh.
[0112] In one embodiment, the electrode assemblies can include
bimodal electrodes as shown in FIG. 6 and described above.
[0113] The components described herein are intended for use in a
automatic sampling device which is configured to be worn like an
ordinary wristwatch. As described in International Publication No.
WO 96/00110, published Jan. 4, 1996, the wristwatch housing
typically contains conductive leads which communicate with the
iontophoretic electrodes and the biosensor electrodes to control
cycling and provide power to the iontophoretic electrodes, and to
detect electrochemical signals produced at the biosensor electrode
surfaces. The wristwatch housing can further include suitable
electronics (e.g., microprocessor, memory, display and other
circuit components) and power sources for operating the automatic
sampling system.
[0114] Further, the sampling system can be pre-programmed to begin
execution of its signal measurements (or other functions) at a
designated time. One application of this feature is to have the
sampling system in contact with a subject and to program the
sampling system to begin sequence execution during the night so
that it is available for calibration immediately upon waking. One
advantage of this feature is that it removes any need to wait for
the sampling system to warm-up before calibrating it.
3. LAMINATES, COLLECTION ASSEMBLIES, AND AUTOSENSOR ASSEMBLIES
[0115] The present invention relates to laminates, collection
assemblies, and autosensors for use in a sampling device. More
particularly, the present laminates, collection assemblies, and
autosensors are used in a transdermal sampling device that is
placed in operative contact with a skin or mucosal surface of the
biological system to obtain a chemical signal associated with an
analyte of interest. The sampling device transdermally extracts the
analyte from the biological system using, for example, an
iontophoretic sampling technique. The transdermal sampling device
can be maintained in operative contact with the skin or mucosal
surface of the biological system to provide such continual or
continuous analyte measurement.
[0116] In one aspect, the invention relates to a collection
assembly for use in a iontophoretic sampling device useful to
monitor a selected analyte, or derivatives thereof, present in a
biological system. The collection assembly can include:
[0117] a) a mask layer comprised of a substantially planar material
that is substantially impermeable to the selected analyte or
derivatives thereof, where the mask layer has inner and outer faces
and the outer face provides contact with the biological system;
[0118] b) a collection insert layer comprised of an ionically
conductive material having first and second surfaces, and
[0119] c) the mask and collection insert layers are configured such
that (i) at least a portion of the collection insert is exposed to
provide contact with the biological system, and (ii) flow of the
analyte through the first surface of the collection insert layer
from the biological system is prevented by the mask layer for any
portion of the first surface of the collection insert layer that is
in contact with the inner face of the mask layer. Such collection
assemblies can be included in autosensor assemblies typically
including (a) the collection assembly, (b) an electrode assembly
having an inner face comprising an electrode and an outer face,
where the inner face of the electrode assembly and the collection
assembly are aligned to define a plurality of flow paths through
said collection assembly, and (c) a support tray that contacts the
outer face of the electrode assembly. One example of this type of
collection assembly and autosensor assembly is described in Example
2.
[0120] In a further aspect, the invention includes a collection
assembly having a mask layer, a collection insert layer comprised
of an ionically conductive material, wherein the layers are axially
aligned to provide a flow path through the collection assembly.
Typically, the mask layer is comprised of a material that is
substantially impermeable to the chemical signal associated with
the analyte of interest. Exemplary embodiments of such collection
assemblies are described in Examples 1 and 2. Example 1 describes
use of a retaining layer as well.
[0121] In one embodiment, the mask layer and retaining layer each
define at least one opening and at least a portion of a collection
insert is exposed by each opening to provide a flow path through
the collection assembly. Further, the collection insert may be
contained by a corral or gasket that contains, seals, or retains
the collection insert at a desired location. When a gasket is used
the entire surface of the collection insert may be exposed, for
example, by the mask layer. In this case the mask layer contacts
the edges of the gasket.
[0122] In another embodiment, the mask layer and retaining layer
each define two openings and at least a portion of a collection
insert is exposed by each opening to provide two flow paths through
the collection assembly. As stated above, the collection inserts
may each be contained by a corral or gasket.
[0123] The mask layer may be coated with an adhesive on either of
its faces or on both of its faces. Further, a liner may be adhered
to one of the faces of the mask layer, typically the outer face.
Similarly for the retaining layer. In one embodiment, (i) the outer
face of the mask layer has an adhesive coating and a liner
attached, (ii) the inner face of the mask layer contacts the
collection inserts and adheres to the inner face of the retaining
layer, and (iii) the outer face of the retaining layer is adhered
to a second liner (e.g., a plow-fold liner).
[0124] The collection assemblies may be prepared as laminates.
Further, other components, such as support trays and electrodes or
electrode assemblies can be combined with the collection assemblies
or laminates to form autosensor assemblies.
[0125] Further, the collection assemblies, laminates, and
autosensors of the invention may be provided in sealed packages.
Such sealed packets may further comprise a source of hydration
(e.g., a hydrating insert) which ensures that the collection
inserts will not dehydrate prior to use.
[0126] The collection assemblies, laminates, and autosensors of the
present invention are particularly well suited for use as
consumable components in the iontophoretic sampling device of FIG.
2. Referring now to FIG. 3, one embodiment of a collection assembly
for use in such a sampling device is generally indicated at 50. The
assembly is aligned with an electrode assembly 60 which includes
both iontophoretic 59 and sensing electrodes 61 as described above.
A tray 70 is adapted to hold the electrode and collection
assemblies in operative alignment, and provides electrical
connection between the electrode assembly and control components
provided by an associated housing element (e.g., housing 32 of FIG.
2). If desired, the tray 70 can be comprised of a substantially
rigid substrate and have features or structures which cooperate
and/or help align the various assemblies in the sampling device.
For example, the tray can have one or more wells or recesses,
and/or one or more lips, rims, or other structures which depend
from the substrate, each of which features or structures facilitate
register between the electrode assembly, the collection assembly
and the associated components of the sampling device. The tray can
be composed of any suitable material, desirable characteristics of
which can include the following: (i) high heat distortion
temperature (to allow hot melt bonding of the electrode assembly to
the tray, if necessary or desired); (ii) optimum rigidity, to allow
for ease of handling and insertion into the housing of the
monitoring device; (iii) low moisture uptake, to insure that proper
hydration of the ionically conductive medium (e.g., hydrogel
collection inserts) is maintained when the medium is stored in
proximity to the tray; and, (iv) moldable by conventional
processing techniques, for example, injection molding.
[0127] Materials for use in manufacturing the tray include, but are
not limited to, the following: PETG (polyethylene terephthalate
copolymer); ABS (acrylonitrile-butadiene-styrene co-polymer); SAN
(styrene-acrylonitrile copolymer); SMA (styrene-maleic anhydride
copolymer); HIPS (high impact polystyrene); polyethylene
terephthalate (PET); polystyrene (PS); polypropylene (PP); and
blends thereof. In a preferred embodiment the tray is formed from
high impact polystyrene.
[0128] The electrode assembly is typically fixed to the tray to,
for example, facilitate register between the electrode assembly and
the associated components of the housing of the sampling device.
The electrode assembly may be manufactured as part of the tray, or,
the electrode assembly may be attached to the tray by, for example,
(i) using connecting means which allow the electrode assembly to
engage the tray (e.g., holes in the electrode assembly with
corresponding pegs on the tray); or (ii) use of an adhesive.
Exemplary adhesives include, but are not limited to, the following:
acrylate, cyanoacrylate, styrene-butadiene, co-polymer based
adhesives, and silicone. In a preferred embodiment the tray is
attached to the electrode assembly as in (i) above with the pegs
deformed, thus locking the components together.
[0129] The collection assembly 50 includes one or more collection
inserts 52 that are comprised of an ionically conductive material.
Each collection insert has first and second opposing surfaces, 54
and 56, respectively. The collection insert is preferably comprised
of a substantially planar hydrogel disk. The first opposing surface
54 of the insert is intended for contact with a target surface
(skin or mucosa), and the second opposing surface 56 is intended
for contact with the electrode assembly 60, thereby establishing a
flow path between the target surface and the iontophoretic and
sensing electrodes. A mask layer 58 is positioned over the first
surface 54 of the collection insert. The mask layer is used to
inhibit contact between the sensing electrode(s) of the electrode
assembly and chemical signal that may be transported in a radial
direction from the target surface. The mask layer 58 comprises at
least one opening 62 which is sized to allow a detectable amount of
chemical signal to reach the sensing electrode, while reducing or
preventing entry of chemical signal into the flow path thorough the
insert that has a potential to be transported (e.g., by diffusion)
in a radial direction toward an edge of the sensing electrode. As
explained in commonly owned U.S. Pat. No. 5,735,273, incorporated
by reference herein, this type of mask layer serves to
substantially eliminate "edge effect" flow, i.e., the mask prevents
chemical signal from contacting the electrode unless the signal
flows substantially perpendicular to the surface of the sensing
electrode. Accordingly, the opening 62 in the mask layer is sized
to expose at least a portion of the first surface 54 of the
collection insert. In the particular embodiment depicted in FIG. 3,
a border region 66 of the mask layer generally extends beyond the
first surface of the collection insert to provide an overhang.
[0130] A retaining layer 68 is positioned in facing relation with
the second surface 56 of the collection insert 52. The retaining
layer has at least one opening 72 which exposes at least a portion
of the second surface 56 of the collection insert. Again, in the
particular embodiment of FIG. 3, a border region 74 of the
retaining layer 68 extends beyond the second surface 56 in order to
provide an overhang. The overhangs provided by the mask and
retaining layers serve as a point of attachment between the two
layers. When these layers are attached to each other at their
overhanging portions, a laminate is formed wherein the collection
insert is sandwiched between the two layers to provide a
three-layer structure. Although the overhangs provided by border
regions 66 and 74 are depicted in FIG. 3 as extending along an edge
of the mask and retaining layers, the overhangs can, of course, be
formed from one or more corresponding tab overhangs (positioned
anywhere on the subject layers), one or more corresponding edges
(opposite and/or adjacent edges), or can be formed from a
continuous overhang which encompasses the collection insert (e.g.,
an overhang which circumscribes an oval- or circular-shaped insert,
or an overhang which surrounds all sides of a square-,
rectangular-, rhomboid-, or triangular-shaped insert).
[0131] The one or more openings 62 in the mask layer, and the one
or more openings 72 in the retaining layer can have any suitable
geometry which is generally dictated by the shape of the collection
insert 52 and/or the shape of the iontophoretic and sensing
electrodes 59 and 61 used in the electrode assembly 60. In the
embodiment depicted in FIG. 3, wherein the electrodes are arranged
in a circular configuration and the collection insert is a circular
disk, openings 62 and 72 preferably have a round, oval, ellipsoid,
or "D"-shape which serves to collimate the flow (i.e., reduce or
eliminate the edge effect flow) of chemical signal as it passes
through the collection assembly toward the electrode assembly
60.
[0132] The openings 62 and 72 in the mask and retaining layers can
be sized the same or differently, wherein the particular sizes of
the openings are generally set by the overall surface area of the
sensing electrode 61 that the collection assembly must operate with
in the sensing device. Although the collection assemblies of the
present invention can be provided in any size suitable for a
targeted skin or mucosal surface, an assembly that is used with a
sampling device that contacts a subject's wrist will generally have
a surface area on each face in the range of about 0.5 cm.sup.2 to
15 cm.sup.2. The openings 62 and 72 generally expose about 50% of
the area of the sensing electrode, within a manufacturing tolerance
of about +20%. In general, the openings constitute an area that is
in the range of 1% to 90% of the surface area encompassed by the
mask or retaining layer plus the opening(s). The openings are,
however, sized smaller than the overall surface of the collection
insert in at least one dimension.
[0133] The size or geometric surface area of the sensing electrode
61, the thickness of the collection insert 52, the sizes of the
openings 62 and 72 in the mask and retaining layers, and the size
of the overhangs provided by border regions 66 and 74 of the mask
and retaining layers are all interrelated to each other. For
example, when the thickness of the collection insert is increased,
the size of the opening is decreased to obtain the same degree of
reduction of edge effect flow (radial transport) of the transported
chemical signal. Any decrease in the size of the openings in the
mask and retaining layers increases the ability to block such
unwanted flow. However, it is also desirable to maximize the size
of the openings in order to maximize the amount of chemical signal
which contacts the reactive surface of the sensing electrode
61.
[0134] The physical characteristics of the mask and retaining
layers are selected so as to optimize the operational performance
of the collection assembly. More particularly, since the assembly
is intended to be contacted with a target surface for an extended
period of time, the layers preferably have sufficient mechanical
integrity so as to provide for such extended use. Furthermore, the
layers should have sufficient flex and stretchability so as to
resist tearing or rupture due to ordinary motion in the target
surface, for example, movement of a subjects arm when the sampling
device is contacted with a forearm or wrist. The layers can also
have, for example, rounded corners which tolerate a greater degree
of twist and flex in a target area (without breaking contact) than
layers which have sharp, angular corners. The layers also provide
for some degree of sealing between the target surface and the
collection assembly 50, and between the collection assembly and the
electrode assembly 60, and can provide for electrical, chemical,
and/or electrochemical isolation between multiple collection
inserts in the collection assembly and their corresponding
electrodes in the electrode assembly. Other physical
characteristics include the degree of occlusivity provided by the
mask layer, adhesion to the target surface and/or electrode
assembly, and mechanical containment of the associated collection
insert(s). In one embodiment, the collection assembly includes two
collection inserts (as depicted in FIG. 3), and the mask and
retaining layers have corresponding central regions, 76 and 78,
respectively, which are disposed between corresponding openings in
the layers and provide for a further point of attachment between
the two layers. As will be appreciated by the skilled artisan upon
reading the present specification, this further point of attachment
provides for chemical and electrical isolation between the two
collection inserts.
[0135] The mask and retaining layers are preferably composed of
materials that are substantially impermeable to the analyte
(chemical signal) to be detected (e.g., glucose); however, the
material can be permeable to other substances. By "substantially
impermeable" is meant that the material reduces or eliminates
chemical signal transport (e.g., by diffusion). The material can
allow for a low level of chemical signal transport, with the
proviso that chemical signal that passes through the material does
not cause significant edge effects at the sensing electrode used in
conjunction with the mask and retaining layers. Examples of
materials that can be used to form the layers include, without
limitation, the following: polymeric materials--such as,
polyethylene (PE) {including, high density polyethylene (HDPE), low
density polyethylene (LDPE), and very low density polyethylene
(VLDPE)}, polyethylene copolymers, thermoplastic elastomers,
silicon elastomers, polyurethane (PU), polypropylene (PP), (PET),
nylon, flexible polyvinylchloride (PVC), and the like; natural
rubber or synthetic rubber, such as latex; and combinations of the
foregoing materials. Of these materials, exemplary flexible
materials include, but are not limited to, the following: HDPE,
LDPE, nylon, PET, PP, and flexible PVC. Stretchable materials
include, but are not limited to, VLDPE, PU, silicone elastomers,
and rubbers (e.g., natural rubbers, synthetic rubbers, and latex).
In addition, adhesive materials, for example, acrylate, styrene
butadiene rubber (SBR) based adhesives, styrene-ethylene-butylene
rubber (SER) based adhesives, and similar pressure sensitive
adhesives, can be used to form layers as well.
[0136] Each layer can be composed of a single material, or can be
composed of two or more materials (e.g., multiple layers of the
same or different materials) to form a chemical signal-impermeable
composition.
[0137] Use of a mask to reduce or eliminate chemical signal which
can radially transport toward a working electrode was described in
co-owned U.S. Pat. Nos. 5,735,273 and 5,827,183, both herein
incorporated by reference in their entireties.
[0138] Methods for making the mask and retaining layers include,
without limitation, extrusion processes, flow and form molding
techniques, die cutting, and stamping techniques, which are all
practiced according to methods well known in the art. Most
preferably, the layers are manufactured in a manner that is the
most economical without compromising performance (e.g.,
impermeability to a chemical signal, the ability to manipulate the
layers by hand without breaking or otherwise compromising
operability, and the like). The layers may further have an adhesive
coating (e.g., a pressure sensitive adhesive) on one or both
surfaces. Exemplary adhesives include, but are not limited to, the
following: starch, acrylate, styrene butadiene rubber-based,
silicone, and the like. Adhesives that may come in contact with
skin have a toxological profile compatible with skin-contact. In an
exemplary embodiment, SBR-adhesive RP100 (John Deal Corporation,
Mount Juliet, Tenn.) can be used on both sides of a 0.001 inch
thick PET film (Melinex #329, DuPont) retaining layer to adhere to
the mask and the other side to the sensor. Another exemplary
embodiment uses acrylate #87-2196 (National Starch and Chemical
Corporation, Bridgewater, N.J.) on the skin side of a 0.002 inch
thick polyurethane (e.g., Dow Pellethane; Dow Chemical Corp.,
Midland, Mich.) mask to adhere the mask to the skin. Further, the
mask and retaining layers may be coated with a material which
absorbs one or more compounds or ions that may be extracted into
the collection insert during sampling.
[0139] Since the collection assemblies of the present invention are
intended for use as consumable (replaceable) components for a
sampling device, the various constituents of the assemblies are
preferably manufactured and then pre-assembled in an easy-to-use
laminate structure that can be inserted and then removed from the
sampling device housing by the consumer. In this regard, after the
mask layer 58, retaining layer 68, and collection insert(s) 56 are
produced, they are aligned as shown in FIG. 3, and the overhangs
provided by borders 66 and 74 are attached to each other to provide
a three-layer laminate which sandwiches the collection insert in
between the mask and retaining layers as described above. The
laminate, or a plurality of such laminates can be provided in a
sealed package in order to maintain the cleanliness of the
collection assembly (e.g., avoid chemical contamination from
manufacturer and/or consumer handling) prior to use, and further to
avoid dehydration of the collection inserts prior to use.
[0140] If desired, the package can include a source of hydration
(e.g., a hydrating insert formed from a water-soaked pad, non-woven
material, or gel which ensures that the collection inserts will not
dehydrate prior to use. The hydrating insert may include other
components as well, such as, buffers and antimicrobial compounds.
The source of hydration is disposed of after the laminate has been
removed from the package, and thus does not typically form a
component of the sampling device.
[0141] The pre-assembled collection assembly laminates can include
one or more optional liners which facilitate handling of the
assembly. For example, a removable liner 80 can be applied over the
mask layer 58, particularly when the mask layer is coated with an
adhesive. An additional removable liner 90 can be applied over the
retaining layer 68. The removable liners 80 and 90 are intended to
remain in place until just prior to use of the assembly, and are
thus manufactured from any suitable material which will not be too
difficult to remove, but which will remain in place during
packaging, shipment and storage to provide added protection to the
assembly. If the mask and/or retaining layers are coated with (or
actually formed from) an adhesive, the removable liners can
preferably be comprised of a polypropylene or treated polyester
material which does not adhere well to commonly used contact
adhesives. Other suitable materials include, without limitation,
water and/or solvent impermeable polymers (including, but not
limited to PET, PP, PE, and the like) and treated metal foils.
[0142] The removable liners 80 and 90 are generally shaped to cover
the outer surfaces of the mask and retaining layers. The liners can
further include grasping means, such as the tab 82 depicted in FIG.
3, and intuitive indicia (such as numbering) which indicates the
order in which the liners are intended to be removed during
assembly of the sampling device. If desired, the liners can be
shaped in a folded "V" (i.e., a "plow-fold" liner, see, e.g., liner
90 of FIG. 3) or "Z" shape which provides a grasping means for the
user, as well as providing for a controlled release motion in the
liner. Alternatively, the liners can have an internal cut (e.g., a
spiral cut extending from one edge of the liner and ending in the
surface of the liner) or a scoring pattern which facilitates
removal of the liner. Particularly, the liner material, shape, and
related cuts or patterns or weakness are selected to ensure that
removal of the liners does not delaminate the collection assembly,
or otherwise disrupt the alignment between the various components
of the collection assembly (i.e., the alignment between the mask
layer, retaining layer, and the collection insert).
[0143] Production of one embodiment of the above-described
collection assembly and autosensor assembly is presented in Example
1.
[0144] Referring now to FIG. 4, a related embodiment of a
collection assembly produced according to the present invention is
generally indicated at 100. The assembly 100 is aligned with an
electrode assembly 110 which includes iontophoretic 109 and sensing
electrodes 111 as described above, and is adapted to be held by a
tray 120 as also described above. The collection assembly 100
includes one or more collection inserts 102 that are comprised of
an ionically conductive material, and each collection insert has
first and second opposing surfaces, 104 and 106, respectively.
[0145] The first opposing surface 104 of the collection insert 102
is intended for contact with a target surface (skin or mucosa), and
the second opposing surface 106 is intended for contact with the
electrode assembly 110, thereby establishing a flow path between
the target surface and the iontophoretic and sensing electrodes. As
above, a mask layer 108 is positioned over the first surface 104 of
the collection insert, and includes one or more openings 112 which
provide for a collimated flow path between the target surface and
the electrode assembly as also described above. The opening 112 in
the mask layer 108 is sized smaller in at least one dimension
relative to the surface area of the collection insert 102.
[0146] A top surface 124 of a second layer 118 is positioned in
facing relation with the bottom surface 114 of mask layer 108. The
second layer comprises a gasket which has at least one opening 122.
A two-layer laminate is formed when the mask and second layers are
attached at their respective facing surfaces. The second layer also
includes the collection insert 102 which is disposed within, and
substantially fills the opening 122.
[0147] The physical and material properties of the mask layer are
substantially identical to those of the mask layer described
hereinabove, and the size and shape of the one or more openings are
also determined using the above selection criteria. Furthermore,
techniques for manufacture and manipulation of the mask layer 108
are substantially identical to those techniques described above.
However, unlike the above-described retaining layer, the gasket in
the second layer 118 of the present embodiment is intended to serve
as a corral for the collection insert. More particularly, the
gasket maintains the collection insert in a particular orientation
such that, when the collection assembly is combined (contacted)
with the electrode assembly, the collection insert is properly
aligned with the iontophoretic and sensing electrodes. The gasket
material further provides for electrical and/or chemical isolation
between multiple collection inserts, and provides structure to the
collection assembly.
[0148] The second layer gasket can be formed from any suitable
material such as those materials used in the mask and retaining
layers of the present invention. The gasket material could be a
foam material that is sized to fit within the dimensions of the
tray 120. Exemplary gasket materials include, without limitation,
PE, PP, PET, nylon, and foamed PE. The gasket material can further
have an adhesive coating or layer which contacts the electrode
assembly and provides for the facile alignment between the
electrode and collection assemblies.
[0149] Optional release liners 130 and/or 140 (a plow-fold liner)
can also be respectively applied against the mask layer 108 and
second layer 118 to facilitate handling of the collection
assemblies as described above. Furthermore, pre-assembled
collection assembly laminates are preferably packaged, either
individually or in groups, as also previously described.
[0150] Referring now to FIG. 5, a still further related embodiment
of a sampling system collection assembly is generally indicated at
150. The collection assembly 150 is aligned with an electrode
assembly 160 which includes iontophoretic 159 and sensing
electrodes 161 as described above, and is adapted to be held by a
tray 170. The collection assembly 150 includes one or more
collection inserts 152 that are comprised of an ionically
conductive material, and each collection insert has first and
second opposing surfaces, 154 and 156, respectively.
[0151] The first opposing surface 154 of the collection insert 152
is intended for contact with a target surface (skin or mucosa), and
the second opposing surface 156 is intended for contact with the
electrode assembly 120, thereby establishing a flow path between
the target surface and the iontophoretic and sensing electrodes. As
above, a mask layer 158 is positioned over the first surface 154 of
the collection insert, and includes one or more openings 162 which
provide for a collimated flow path between the target surface and
the electrode assembly as also described above. The opening 162 in
the mask layer 158 is sized smaller in at least one dimension
relative to the surface area of the collection insert 152.
[0152] A top surface 174 of a second layer 168 is positioned in
facing relation with the bottom surface 164 of the mask layer 158.
The second layer comprises a gasket which has at least one opening
172. The second layer also includes the collection insert 152 which
is disposed within, and substantially fills the opening 172.
[0153] The collection assembly 150 further includes a retaining
layer 178, having a top surface 180 that is positioned in facing
relation with the bottom surface 176 of the second layer 168. The
retaining layer has at least one opening 182 which exposes at least
a portion of the second surface 156 of the collection insert 152.
When the corresponding surfaces of the mask layer and second layer
are attached to each other, and the corresponding surfaces of the
second layer and the retaining layer are attached to each other, a
laminate is formed wherein both the second layer and the collection
insert are sandwiched between the mask and retaining layers to
provide a three-layer structure.
[0154] The physical and material properties of the mask and
retaining layers are substantially identical to those of the mask
and retaining layers described hereinabove, and the size and shape
of the one or more openings are also determined using the above
selection criteria. Furthermore, techniques for manufacture and
manipulation of the mask and retaining layers 158 and 178 are
substantially identical to those techniques described above.
Furthermore, the physical and material properties of the second
layer gasket are substantially identical to those described
above.
[0155] Optional release liners can also be applied against the mask
layer 158 and retaining layer 178 to facilitate handling of the
collection assemblies as described above. Furthermore,
pre-assembled collection assembly laminates are preferably
packaged, either individually or in groups, as also previously
described.
EXPERIMENTAL
[0156] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the description above as well as the examples which
follow are intended to illustrate and not limit the scope of the
invention. Other aspects, advantages and modifications within the
scope of the invention will be apparent to those skilled in the art
to which the invention pertains.
[0157] In the following examples, efforts have been made to ensure
accuracy with respect to numbers used (e.g., amounts, temperature,
etc.) but some experimental error and deviation should be accounted
for. Unless indicated otherwise, temperature is in degrees C and
pressure is at or near atmospheric.
[0158] All patents, patent applications, and publications mentioned
herein, both supra and infra, are hereby incorporated by
reference.
EXAMPLE 1
An Exemplary Autosensor Assembly
[0159] A tray was produced using a high impact polystyrene (e.g.,
Chevron Valtra HG200N02; Chevron Chemical Corp., Houston, Tex.) in
a plastic injection molding process. General shape and dimensions
of the tray are indicated in FIG. 8A (the tray was 0.110 inches
thick, with raised areas indicated in the figure). Dimensions in
FIGS. 8A to 8H are all given in inches.
[0160] An electrode assembly was produced using thick film ink
formulations in a screen printing process. Each ink formulation
comprised: a) an electrically conductive particulate, b) an
electrochemically active particulate, c) a polymeric binder, and d)
a volatile organic solvent to create a liquid slurry. During screen
printing, the inks were patterned onto the polyethylene
terephthalate (PET; e.g., Melinex ST507, Dupont deNemours,
Wilmington, Del.) substrate and dried in place by passing through
convection ovens. General shape and dimensions of the electrode
assembly are indicated in FIGS. 8B (the sensor is shown as lying
flat for clarity; the material was polymer thick film inks on a
0.005 inch thick PET substrate).
[0161] The tray and electrode assembly were aligned using precisely
punched holes in the sensor substrate that engage with molded-in
pins in the tray. The pins were plastically deformed (staked) with
a blunt metal punch to fix the sensor substrate to the tray.
[0162] A tri-layer laminate was produced as follows (FIGS. 8C, 8D,
and 8E). A mask layer, having the general shape and dimensions
shown in FIG. 8C, was produced from a 0.002 inch thick polyurethane
film (e.g., Dow Pellethane #2363-80AE; Dow Chemical Corp., Midland,
Mich.) coated on one side with an 0.001 inch layer of acrylic
pressure sensitive adhesive (e.g., Duro-tak, #87-2196; National
Starch and Chemical Corporation, Bridgewater, N.J.). A rotary die
cutting press was used to create the circular openings, to create
the outline border/perimeter geometry, and to laminate the mask
material to the patient liner roll stock (0.003 inch thick PET
coated on one side with silicone release; e.g., Fox River #1730
(Fox River Associates, Geneva, Ill.).
[0163] The collection inserts were two essentially circular
hydrogel disks, illustrated in FIG. 8D, made from a water solution
of polyethylene oxide, phosphate buffer, and glucose oxidase,
impregnated in a 0.004 inch thick nonwoven PET (e.g., Remay.TM.
#2250). This composite began as roll stock from which circular
discs were cut and placed into contact with the mask material using
a male-female punch set.
[0164] A retaining layer, having the general shape and dimensions
shown in FIG. 8E, was produced from 0.001 inch thick PET film
(e.g., DuPont Melinex #329; Dupont deNemours, Wilmington, Del.)
coated on both sides with a styrene-butadiene-based pressure
sensitive adhesive (e.g., RP100; John Deal Corporation, Mount
Juliet, Tenn.). A rotary die cutting press was used to create the
circular openings and outline border/perimeter geometry. A
laminating press was used to place the retaining layer in contact
with the collection insert and mask.
[0165] The openings in the mask layer were sized to expose a
portion of the surface of each collection insert. A border region
of the mask layer extended beyond the first surfaces of the
collection insert to provide an overhang. The retaining layer was
positioned in facing relation with the second surfaces of the
collection insert. The retaining layer had two openings which
exposes portions of the second surfaces of the collection insert. A
border region of the retaining layer extended beyond the second
surfaces of the collection insert in order to provide an overhang.
The overhanging portions of the mask and retaining layer served as
points of attachment where the retaining layer adhesive bound to
the non-adhesive surface of the mask and thus prevented movement.
This attaching of the layers to each other at their overhanging
portions created a laminate where the collection insert was
sandwiched between the two layers to provide a three-layer
structure.
[0166] The mask layer perimeter extended beyond the retaining layer
perimeter, thus creating a third overhang. This overhang allows the
mask layer to conform to the contours of the biological system to
which it is contacted (for example, a human forearm) and to be
unencumbered by the rigidity of other parts of the autosensor
assembly (for example, the tray and electrodes). Superior adhesion
and reduced irritation were achieved by employing such an
overhang.
[0167] The outline geometry of the patient liner, shown in FIG. 8F,
was produced during a blanking operation that used steel rule dies
to cut the patient liner roll stock.
[0168] A second liner, i.e., a plow-fold liner, for contacting the
retaining layer and collection inserts was produced from 0.0016
inch thick biaxially oriented polypropylene film coated on one side
with silicone release (e.g., Fox River, #1803; Fox River
Associates). The treated side of the plowfold liner faced the
collection inserts, retaining layer, and sensor. This film was
folded and perforated to length on a rotary press. The folded film
was pulled apart at its perforations to create single liners and
was laminated to the outer adhesive surface of the retaining layer
(dimensions shown in FIG. 8G).
[0169] The plowfold liner, as described, left a portion of the
retaining layer adhesive exposed. This adhesive was pressed into
contact with the electrode-to-tray assembly during the plowfold
lamination process, thus adhering the tri-layer laminate with
liners to the electrode-to-tray assembly. A custom-designed
assembly machine performed the lamination using fixtures to
precisely align the components relative to each other. Each
component part nested precisely within its respective fixture to
provide the necessary alignment. Vacuum was used to keep the parts
from falling out of their fixtures during assembly.
[0170] The entire assembly described above (FIG. 8H), including,
the tray, electrode assembly, tri-layer laminate, and liners,
comprises an exemplary autosensor assembly of the present
invention.
[0171] This particular embodiment of the autosensor assembly is
also graphically represented in FIG. 3 and FIGS. 8A-8H and is
intended for use in the Glucowatch.RTM. biographer (Cygnus, Inc.,
Redwood City, Calif.), an iontophoretic sampling system for glucose
concentration monitoring of a subject.
[0172] Alternative materials for the components described above
include, but are not limited to, the following:
[0173] (i) Alternate Mask, Retaining Layer, Patient Liner, and
Plowfold Liner Materials: high density polyethylene (HDPE), low
density polyethylene (LDPE), very low density polyethylene (VLDPE),
polyethylene copolymers, thermoplastic elastomers, silicon
elastomers, polyurethane (PU), polypropylene (PP), (PET), nylon,
flexible polyvinylchloride (PVC), natural rubber, synthetic rubber,
and suitable combinations of the foregoing materials.
[0174] (ii) Base films: polyurethane, polyethylene (high density,
medium density, low density, very low density, linear low density,
very low density linear), polyethylene terephthalate (PET,
polyester), vinyl, polystyrene, polycarbonate, diacetate, paper
products, blends of these materials, foam films made from any of
the same materials;
[0175] (iii) Adhesives: acrylic based pressure-sensitive, rubber
based pressure-sensitive (for example, styrene butadiene rubber
(SBR) based adhesives, styrene-ethylene-butylene rubber (SEBR)
based adhesives), cyanoacrylates, epoxies, acrylate, and other
pressure sensitive adhesives.
[0176] (iv) Release coatings: silicone, florinated polymers,
chlorinated polymers; and
[0177] (v) Alternate tray materials: polycarbonate; PETG
(polyethylene terephthalate copolymer); ABS
(acrylonitrile-butadiene-styrene co-polymer); SAN
(styrene-acrylonitrile copolymer); SMA (styrene-maleic anhydride
copolymer); HIPS (high impact polystryrene); polyethylene
terephthalate (PET); polystyrene (PS); polypropylene (PP); and
blends thereof.
EXAMPLE 2
Another Embodiment of the Autosensor Assembly
[0178] A tray is produced using a high impact polystyrene (e.g.,
Chevron HG200N02) in a plastic injection molding process. General
shape and dimensions of the tray are indicated in FIG. 9A (the tray
was 0.110 inches thick, with raised areas indicated in the figure).
Dimensions in all FIGS. 9A to 9G are given in inches.
[0179] Sensor-to-tray is assembled as described in Example 1. All
other components are made by cutting from sheet stock using still
rule dies, and hand assembled using visual alignment.
[0180] An electrode assembly is produced using thick film ink
formulations in a screen printing process. Each ink formulation
comprises: a) an electrically conductive particulate b) an
electrochemically active particulate, c) a polymeric binder, and d)
a volatile organic solvent to create a liquid slurry. During screen
printing, the inks are patterned onto the polyethylene
terephthalate (PET) substrate and dried in place by passing through
convection ovens. General shape and dimensions of the electrode
assembly are indicated in FIG. 9B (the sensor is shown as lying
flat for clarity; the material is polymer thick film inks on a
0.005 inch thick PET substrate).
[0181] The tray and electrode assembly are aligned using precisely
punched holes in the sensor substrate that engage with molded-in
pins in the tray. The pins are plastically deformed (staked) with a
blunt metal punch to fix the sensor substrate to the tray.
[0182] A mask layer having the general shape and dimensions shown
in FIG. 9C is produced (steel-rule die cut from sheet stock) from
0.0015 inch Deerfield natural HDPE coated on two side with 0.001
inch adhesive (e.g., Duro-tak.TM., #87-2196; National Starch and
Chemical Corporation, Bridgewater, N.J.).
[0183] The collection inserts are two essentially circular hydrogel
disks, illustrated in FIG. 9D, made from a water solution of
polyethylene oxide, phosphate buffer, and glucose oxidase,
impregnated in a 0.004 inch thick nonwoven PET (e.g., Remay.TM.
#2250). This composite begins as roll stock from which circular
discs are steel-rule die cut.
[0184] A plowfold liner having the general shape and dimensions
shown in FIG. 9E is produced from 0.0016 inch thick biaxially
oriented polypropylene film coated on one side with silicone
release (e.g., Fox River, #1803; Fox River Associates). This film
is folded and perforated to length on a rotary press. The folded
film is pulled apart at its perforations to create single liners
and is laminated to the outer adhesive surface of the retaining
layer.
[0185] A patient liner having the general shape and dimensions
shown in FIG. 9F is produced (steel-rule die cut from sheet stock)
from, for example, 0.003 inch Fox River (#1806) PET coated on one
side (facing/contacting the mask) with silicone release.
[0186] The components are assembled in the following order from the
bottom up (for example, using manual assembly and human visual
alignment): (1) sensor-to-tray assembly; (2) plowfold liner; (3)
gel disks (collection inserts); (4) mask layer; and (5) patient
liner.
[0187] FIG. 9G shows a plan view of the assembly just described
with all components showing.
[0188] Accordingly, novel laminates, collection assemblies, and
autosensor assemblies are disclosed. Although preferred embodiments
of the subject invention have been described in some detail, it is
understood that obvious variations can be made without departing
from the spirit and the scope of the invention as defined by the
appended claims.
* * * * *