U.S. patent application number 16/005826 was filed with the patent office on 2018-10-11 for microfluidic systems for electrochemical transdermal analyte sensing using a capillary-located electrode.
This patent application is currently assigned to Georgetown Univerity. The applicant listed for this patent is Georgetown University. Invention is credited to Makarand Paranjape.
Application Number | 20180289299 16/005826 |
Document ID | / |
Family ID | 51580627 |
Filed Date | 2018-10-11 |
United States Patent
Application |
20180289299 |
Kind Code |
A1 |
Paranjape; Makarand |
October 11, 2018 |
Microfluidic Systems For Electrochemical Transdermal Analyte
Sensing Using a Capillary-Located Electrode
Abstract
A sensing device, designed to be used in contact with the skin,
contains a plurality of individually controllable sites for
electrochemically monitoring an analyte, such as glucose, in
interstitial fluid of a user. The device includes at least a
hydrophobic layer designed to contact the skin; a capillary channel
providing an opening adjacent the skin; a metal electrode layer
having a sensor layer applied to an edge portion thereof such that
it is exposed to the interior of said capillary channel, the
sensing layer being effective to measure the analyte.
Inventors: |
Paranjape; Makarand; (Silver
Spring, MD) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Georgetown University |
Washington |
DC |
US |
|
|
Assignee: |
Georgetown Univerity
Washington
DC
|
Family ID: |
51580627 |
Appl. No.: |
16/005826 |
Filed: |
June 12, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13834199 |
Mar 15, 2013 |
10004434 |
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16005826 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/1491 20130101;
A61B 5/1486 20130101; A61B 5/14532 20130101; A61B 5/14514 20130101;
A61B 5/1477 20130101 |
International
Class: |
A61B 5/145 20060101
A61B005/145; A61B 5/1491 20060101 A61B005/1491; A61B 5/1477
20060101 A61B005/1477; A61B 5/1486 20060101 A61B005/1486 |
Claims
1. A sensing device comprising a plurality of individually
controllable detection sites for electrochemically monitoring an
analyte in interstitial fluid of a user, each individually
controllable detection site comprising: a dual opening capillary
channel traversing multiple layers and having one of the dual
openings located adjacent to the skin of the user, the multiple
layers including at least a hydrophobic layer, designed to contact
the skin, and a metal electrode layer, wherein the metal electrode
layer is discontinuous at a circumference of the capillary channel,
such that two non-contiguous edge portions of the metal electrode
layer are present within the circumference of said channel; and a
first non-contiguous edge portion of the metal electrode layer
including a sensing layer applied thereto and being exposed to an
interior of the capillary channel, wherein the sensing layer is
effective to measure the analyte within interstitial fluid of the
user entering the capillary channel and contacting the first
non-contiguous edge portion including the sensing layer.
2. The sensing device of claim 1, further comprising: a microheater
located adjacent said hydrophobic layer, the microheater being
effective to produce heat when a sufficient voltage is applied
thereto to ablate the stratum corneum of the underlying skin and
access the interstitial fluid containing the analyte.
3. The sensing device of claim 1, wherein the hydrophobic layer is
silicone.
4. The sensing device of claim 1, wherein the first structural
layer is selected from the group consisting of glass and a
ceramic-like material.
5. The sensing device of claim 1, wherein the metal electrode layer
is selected from the group consisting of gold and platinum.
6. The sensing device of claim 5, wherein the sensing layer is a
conducting polymer.
7. The sensing device of claim 6, wherein the conducting polymer is
polypyrrole (PPy).
8. The sensing device of claim 7, wherein the polypyrrole (PPy) is
modified with glucose oxidase (GOx).
9. The sensing device of claim 8, wherein the polypyrrole (PPy) is
modified with glucose oxidase (GOx) is co-deposited on the edge of
the metal electrode layer with a mediator.
10. The sensing device of claim 9, wherein the mediator is
ferricyanide.
11. A method for electrochemically monitoring an analyte in
interstitial fluid of a user, the method comprising: contacting the
user's skin with a monitoring device, the monitoring device
including a plurality of individually controllable detection sites
for electrochemically monitoring the analyte in interstitial fluid
of a user; controlling at least a first of the individually
controlled detection sites to apply a first voltage to a
microheater located adjacent to the user's skin at the first of the
individually controlled detection sites, wherein the microheater
produces heat responsive to the applied first voltage, the heat
being sufficient to ablate the stratum corneum of the underlying
skin and access the interstitial fluid of the user containing the
analyte; receiving the accessed interstitial fluid at a first
opening of a dual opening capillary channel of the first of the
individually controlled detection sites, wherein the accessed
interstitial fluid rises through the capillary channel, traversing
multiple material layers including at least a hydrophobic layer
contacting the user's skin, first structural layer and a metal
electrode layer that is discontinuous at a circumference of the
capillary channel, such that two non-contiguous edge portions of
the metal electrode layer are present within the circumference of
said capillary channel, a first non-contiguous edge portion of the
metal electrode layer including a sensing layer applied thereto and
being exposed to an interior of the capillary channel; applying a
second voltage between the two non-contiguous edge portions of the
metal electrode layer when the interstitial fluid passes thereby
within the capillary channel; and electronically detecting the
analyte in the interstitial fluid using the sensing layer
responsive to the application of the second voltage.
12. The method of claim 11, further comprising applying the first
voltage for approximately 30 msec.
13. The method of claim 12, wherein the first voltage is about
3V.
14. The method of claim 11, wherein the second voltage is about 0.2
to 0.4 V.
15. The method of claim 11, wherein the hydrophobic layer is
silicone.
16. The method of claim 11, wherein the first structural layer is
selected from the group consisting of glass and a ceramic-like
material.
17. The method of claim 11, wherein the metal electrode layer is
selected from the group consisting of gold and platinum.
18. The method of claim 17, wherein the sensing layer is a
conducting polymer.
19. The method of claim 18, wherein the conducting polymer is
polypyrrole (PPy).
20. The method of claim 19, wherein the polypyrrole (PPy) is
modified with glucose oxidase (GOx).
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
13/834,199 filed Mar. 15, 2013 and titled "Microfluidic Systems For
Electrochemical Transdermal Analyte Sensing Using a
Capillary-Located Electrode," which is incorporated herein by
reference in its entirety.
FIELD OF EMBODIMENTS
[0002] The present embodiments relate generally to non-invasive or
minimally invasive transdermal measurement systems. More
specifically, the embodiments relate to microfluidic transdermal
glucose measurement systems in which a thin electrode is contained
within a fluid-transmitted capillary, and processes for their
production and use.
BACKGROUND
[0003] Minimally invasive transdermal systems are described in, for
example, co-owned U.S. Pat. Nos. 6,887,202 and 7,931,592, both
entitled "Systems and Methods for Monitoring Health and Delivering
Drugs Transdermally," as well as co-owned U.S. application Ser. No.
13/459,392, each of which is incorporated herein by reference in
its entirety. These systems, like the embodiments described herein,
provide for a minimally invasive sampling technique and device
suitable for rapid, inexpensive, unobtrusive, and pain-free
monitoring of important biomedical markers, such as glucose.
[0004] Existing systems remain open to improvement in various
aspects, including consistency in sampling and measurement.
SUMMARY
[0005] A sensing device, designed to be used in contact with the
skin, is provided. The device contains a plurality of individually
controllable sites for electrochemically monitoring an analyte,
such as glucose, in interstitial fluid of a user. The device
includes:
[0006] a hydrophobic layer, designed to contact the skin; an
overlaying first structural layer;
[0007] an overlaying metal electrode layer;
[0008] an overlaying second structural layer;
[0009] for each such detection site, a capillary channel traversing
these layers, thus providing an opening adjacent the skin;
[0010] wherein said metal electrode layer is discontinuous at the
circumference of said capillary channel, such that two
non-contiguous edge portions of electrode are present within the
circumference of said channel;
[0011] applied to one such edge portion of the metal electrode
layer, such that it is exposed to the interior of said capillary
channel, a sensing layer effective to measure said analyte; and
surrounding the lower end of said capillary channel, adjacent said
hydrophobic layer, an electronic element (microheater) effective to
produce heat when a sufficient voltage is applied thereto.
[0012] Also provided are electrical conduits and contacts such that
a voltage can be applied to the microheater, and an additional
voltage can be applied between the two edge portions of the
electrode layer, and an electrochemical response from the sensing
material/electrode layer, indicative of the concentration of
analyte in the sample fluid, can be detected.
[0013] In selected embodiments, the hydrophobic layer is
hydrophobic silicone. The first structural layer may be a glass or
ceramic-like material. The metal electrode layer is preferably gold
or platinum, and the sensing layer, for use in detecting glucose,
is preferably a conducting polymer, such as polypyrrole (PPy),
modified with glucose oxidase (GOx), and preferably further
containing an effective amount of a mediator such as ferricyanide.
The second structural layer is preferably non-absorbent and/or
hydrophobic, and may also be a layer of hydrophobic silicone.
[0014] The diameter of the capillary channel, in one embodiment, is
about 50 .mu.m.
[0015] The thickness of the metal electrode layer is generally in
the range of 100 nm to 1 micron range, e.g. 100-500 nm, 500-1000
nm, 500-800 nm, 250-750 nm, 300-500 nm, etc. An exemplary thickness
is about 500 nm. The structural layers generally have thicknesses
such that the overall thickness of the device is about 1 mm or
less.
[0016] The thickness of the applied sensing layer, measured in a
direction perpendicular to the capillary channel length, may be 200
nm or less, 100 nm or less, or 50 nm or less, in selected
embodiments.
[0017] In use, a voltage is applied to the microheater sufficient
to ablate the stratum corneum of the underlying skin, e.g. a
voltage of about 3 V, typically for about 30 msec. This ablation
allows interstitial fluid to enter the capillary channel, where it
rises via both capillary action and the body's hydrostatic pressure
and contacts the sensing material (e.g. PPy/GOx) within the
capillary. A second voltage, typically 0.2-0.4 V, is applied to the
electrode layer, i.e. between the two above-described edge portions
of the electrode layer, and the level of analyte (e.g. glucose)
contacting the sensing material is electrochemically detected, in
accordance with known methods.
BRIEF DESCRIPTION OF THE DRAWING
[0018] FIG. 1 illustrates an embodiment of a sensing device as
disclosed herein.
DETAILED DESCRIPTION
[0019] A section of an exemplary sensing device, designed to be
used in contact with the skin, is shown in FIG. 1. The device
typically contains a plurality of individually controllable sites,
of which one is illustrated in the FIGURE, for electrochemically
monitoring an analyte, such as glucose, in interstitial fluid of a
user. The device, in a preferred embodiment, includes:
[0020] a hydrophobic layer 12, designed to contact the skin;
[0021] an overlaying first structural layer 14;
[0022] an overlaying metal electrode layer 16;
[0023] an overlaying second structural layer 18;
[0024] a capillary channel 20 traversing these layers, thus
providing an opening adjacent the skin;
[0025] wherein said metal electrode layer is discontinuous at the
circumference of said capillary channel, such that two
non-contiguous edge portions of electrode are present within the
circumference of said channel;
[0026] applied to one such edge portion of the metal electrode
layer, such that it is exposed to the interior of said capillary
channel, a sensing layer 22 effective to measure said analyte;
and
[0027] surrounding the lower end of said capillary channel,
adjacent to said hydrophobic layer, an electronic element
(microheater) 24, effective to produce heat when a sufficient
voltage is applied thereto.
[0028] The diameter of the capillary channel, in one embodiment, is
about 50 .mu.m.
[0029] The thickness of the metal electrode layer is generally in
the range of 100 nm to 1 micron range, e.g. 100-500 nm, 500-1000
nm, 500-800 nm, 250-750 nm, 300-500 nm, etc. An exemplary thickness
is about 500 nm. The thickness of the structural layers is not
generally critical (although layer 12 should be sufficiently thick
to insulate sensing material 22 from heat produced by microheater
24), but these may also be in the general range of hundreds of nm,
e.g. 100-500 nm, 500-1000 nm, 500-800 nm, 250-750 nm, 300-500 nm,
etc. The overall thickness of the device is generally less than 1
mm.
[0030] The diameter of the capillary channel 20, in one embodiment,
is about 50 .mu.m. Other diameter ranges, e.g. 10-100 .mu.m, or
25-75 .mu.m, could also be effective.
[0031] Also provided, though not shown in the FIGURE, are
electrical conduits and contacts such that a voltage can be applied
to the microheater, and an additional voltage can be applied to the
electrode layer (i.e. between the two above-described edge portions
of the electrode layer), and an electrochemical response from the
sensing material/electrode layer, indicative of the concentration
of analyte in the sample fluid, can be detected. The multiple
detection sites within a device are preferably individually
controllable; i.e. voltages can be selectively applied to a given
detection site or sites by a user of the device.
[0032] In selected embodiments, the hydrophobic layer 12 is
hydrophobic silicone, though any biocompatible/non-irritating
hydrophobic material can be used. The structural layer 14 may be a
glass or ceramic-like material, which provides thermal insulation
between the microheater 24 and sensing material 22, or other
structurally stable, nonabsorbent, preferably thermally insulating
material. The metal electrode layer 16 is preferably gold or
platinum.
[0033] A sensing layer 22 effective to measure the analyte is
present on one of the above-described edge portions of the metal
electrode layer, such that it the sensing material is exposed to
the interior of the capillary channel. The sensing layer 22, for
use in detecting glucose, is preferably a conducting polymer, such
as polypyrrole (PPy), modified with the enzyme glucose oxidase
(GOx).
[0034] Preferably, in fabrication, the PPy-GOx layer is
electrodeposited, in accordance with known methods (see, e.g., Liu
et al., Matl. Sci. Eng. C 27(1):47-60 (January 2007); Yamada, et
al., Chem. Lett. 26(3):201-202 (1997); Fortier, et al., Biosens.
Bioelectronics 5:473-490 (1990)) as an extremely thin layer on an
exposed face of the metal electrode, as shown in the FIGURE.
Measuring in the direction perpendicular to the capillary length,
the thickness of the applied layer may be, e.g. 200 nm or less, 100
nm or less, or 50 nm or less, in selected embodiments.
[0035] In one embodiment, a mediator such as ferricyanide, as known
in the art, is co-deposited along with the PPy and GOx. This system
allows electrochemical measurement of the analyte to be carried out
at a voltage of about 0.2-0.4V. A somewhat higher voltage (e.g. 0.7
V), which can lead to interference from other molecules in the
interstitial fluid, would typically be required without the
mediator. Other electron-accepting mediators known in the art for
use with GOx include ferrocene derivatives, conducting organic
salts such as tetrathiafulvalen-tetracycloquinodimethane
(TTF-TCNQ), quinone compounds, phenothiazine compounds, and
phenoxazine compounds.
[0036] The multilayer structure of the device containing the
capillary channels can be fabricated by known deposition and
etching methods. The sensing material 22 is, in one embodiment,
applied by electrodeposition to one of the exposed edges of the
gold electrode within the formed capillary channel 20, as noted
above. As noted above, two noncontiguous edges of electrode are
present within the microchannel, to allow for electrochemical
detection. These edges could be visualized as two distinct
semicircles within the inner surface of the channel, one of which
is treated with the sensing material.
[0037] In use, a voltage is applied to the microheater sufficient
to ablate the stratum corneum of the underlying skin, e.g. a
voltage of about 3 V, typically for about 30 msec. This ablation
(which typically produces a temperature of about 130.degree. C.)
allows interstitial fluid to enter the capillary channel, where it
rises via capillary action and hydrostatic pressure and contacts
the sensing material (e.g. PPy/GOx) within the capillary. A second
voltage, typically 0.2-0.4 V, is then applied between the two
above-described edge portions of the electrode layer), and the
level of analyte (e.g. glucose) contacting the sensing material is
electronically detected, preferably amperometrically detected, in
accordance with known methods.
[0038] The device design presents various advantages, including the
following. The sensor electrode pair, including the metal (e.g.
gold) electrode and PPy/GOx-treated electrode (i.e. the two edge
regions described above, one treated with sensor material), are
located within the microcapillary channel and thus separated
spatially from the microheater. This configuration avoids possible
heat degradation of the enzyme. Further to this aspect, structural
layer 14 is preferably formed of a heat-insulting material, such as
a glass or ceramic material.
[0039] The detection of glucose is typically realized using
chronoamperometry (measurement of current generated versus time for
a voltage step). Ideally, every glucose molecule reaching the GOx
sensing electrode should immediately release its electrons to
produce the measured current. To achieve this condition, the
electrode should have a low surface area to sample volume ratio, to
ensure that glucose is not depleted in the vicinity of the sensing
electrode during analysis. Accordingly, the sensing electrode is
fabricated to be extremely small; i.e. essentially the width of the
metal electrode layer 16, as shown in the FIGURE. Preferred
thicknesses (measured in the direction perpendicular to the channel
length) of the applied sensor layer 22 may be, e.g. 200 nm or less,
100 nm or less, or 50 nm or less, in selected embodiments, in the
100 nm to 1 micron range, e.g. 500 nm. Diffusion times (i.e. the
time for glucose molecules to reach the GOx enzyme) are reduced for
similar reasons.
[0040] In general, the thickness of a metal layer applied via
conventional metal deposition methods, e.g. electrodeposition or
vapor deposition, can be precisely controlled, as compared to
control of lateral dimensions of the planar surface area.
Accordingly, high consistency in the effective sensor area (which
is, again, the width dimension of the metal electrode layer 16), as
well as roughness of the electrode layer, is achieved, giving high
consistency between one sensor element and another, within a single
device or between different devices. In fabrication of the
multilayer device, the gold thickness can be easily reproduced with
very little sidewall imperfections/roughness, and the exposed
region (at the capillary wall) becomes the sensor electrode
area.
[0041] Although glass/ceramic/polymeric substrate layers are
exemplified, other materials, such as paper or other cellulose
substrates, electrospun fibers, or other polymers, could also be
used for the non-metal layers (12, 14, 18) in the device. However,
surfaces contacting the skin, such as the lower surface of layer
12, should be non-absorbent and preferably hydrophobic in nature,
in order to direct fluid flow from the skin into and though the
capillary channel 20 to the sensing material 22. Methods of
treating materials such as paper to render selected portions
hydrophobic and/or non-absorbent are known in the art; see, e.g.
Martinez, et al., Anal. Chem. 2010, 82, 3-10. The surface of
structural layer 12 contacting the interior of the microchannel
should be non-absorbent but should not repel water, so that sample
fluid travels efficiently to the sensing area without volume
loss.
[0042] Integrated circuitry (IC), including radio frequency (RF)
communication capability, may be included peripheral to the device
in order to transmit data readings to a remote location. By way of
example, this transmission may employ Bluetooth devices, or it may
be facilitated as part of a home area network (HAN) in a first
instance, e.g., using protocols such as those described as part of
the Zigbee standards. Further still, the data readings may be
further transmitted outside of the HAN in accordance with a home
health or telehealth communications system using existing wide area
networks (WANs) such as the Internet.
[0043] One skilled in the art recognizes the other areas of
application for the devices described herein. While the examples
specifically described herein are directed to glucose monitoring,
adaptations could be made to ascertain other information from the
biomolecules and biomarkers in the interstitial fluid. For example,
the individual sites could monitor for infectious disease
(microbial, fungal, viral); hazardous compounds; heart or stroke
indicators (troponin, C-reactive protein); chemical or biological
toxins; cancer markers (PSA, estrogen); drug efficacy and dosing
(metabolites): and the like. Such applications of the device as
described are considered to be within the scope of the present
invention.
* * * * *