U.S. patent application number 15/377407 was filed with the patent office on 2017-03-30 for on-body microsensor for biomonitoring.
This patent application is currently assigned to Sano Intelligence, Inc.. The applicant listed for this patent is Sano Intelligence, Inc.. Invention is credited to Matthew Chapman, Hooman Hafezi, Weldon Hall, Scott Miller, Ashwin Pushpala, Alan Szmodis.
Application Number | 20170086724 15/377407 |
Document ID | / |
Family ID | 51520634 |
Filed Date | 2017-03-30 |
United States Patent
Application |
20170086724 |
Kind Code |
A1 |
Pushpala; Ashwin ; et
al. |
March 30, 2017 |
ON-BODY MICROSENSOR FOR BIOMONITORING
Abstract
A microsensor and method of manufacture for a microsensor,
comprising an array of filaments, wherein each filament of the
array of filaments comprises a substrate and a conductive layer
coupled to the substrate and configured to facilitate analyte
detection. Each filament of the array of filaments can further
comprise an insulating layer configured to isolate regions defined
by the conductive layer for analyte detection, a sensing layer
coupled to the conductive layer, configured to enable transduction
of an ionic concentration to an electronic voltage, and a selective
coating coupled to the sensing layer, configured to facilitate
detection of specific target analytes/ions. The microsensor
facilitates detection of at least one analyte present in a body
fluid of a user interfacing with the microsensor.
Inventors: |
Pushpala; Ashwin; (San
Francisco, CA) ; Szmodis; Alan; (San Francisco,
CA) ; Chapman; Matthew; (San Francisco, CA) ;
Hall; Weldon; (San Francisco, CA) ; Miller;
Scott; (San Francisco, CA) ; Hafezi; Hooman;
(San Francisco, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sano Intelligence, Inc. |
San Francisco |
CA |
US |
|
|
Assignee: |
Sano Intelligence, Inc.
San Francisco
CA
|
Family ID: |
51520634 |
Appl. No.: |
15/377407 |
Filed: |
December 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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14876692 |
Oct 6, 2015 |
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15377407 |
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14211404 |
Mar 14, 2014 |
9182368 |
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14876692 |
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61905583 |
Nov 18, 2013 |
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61781754 |
Mar 14, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61B 5/14514 20130101;
G01N 27/3271 20130101; A61B 5/14546 20130101; A61B 5/150969
20130101; A61M 25/00 20130101; A61B 5/14532 20130101; A61M
2037/0023 20130101; A61M 2037/0053 20130101; A61M 2037/0046
20130101; A61B 5/150427 20130101; A61B 5/14503 20130101; C12Q 1/006
20130101; A61B 5/4839 20130101; A61B 5/685 20130101; A61B 5/150022
20130101; A61B 2562/12 20130101; A61M 37/0015 20130101; Y10T
29/49117 20150115; A61B 5/150984 20130101; A61B 5/14865 20130101;
A61B 5/150282 20130101; A61B 2562/125 20130101; A61B 2562/028
20130101; A61B 5/1495 20130101 |
International
Class: |
A61B 5/1486 20060101
A61B005/1486; C12Q 1/00 20060101 C12Q001/00; A61B 5/00 20060101
A61B005/00; G01N 27/327 20060101 G01N027/327; A61B 5/145 20060101
A61B005/145; A61B 5/15 20060101 A61B005/15 |
Claims
1. A sensor for sensing analytes present in a body fluid of a user,
the sensor comprising: a substrate; and a filament comprising: a
substrate core comprising: a columnar protrusion having a base end,
coupled to the substrate, and a distal portion operable to provide
access to the body fluid of the user during operation of the
sensor; a conductive layer, isolated to the distal portion of the
substrate core and away from the base end as an active region
operable to transmit electronic signals generated upon detection of
an analyte within the body fluid; an insulating layer surrounding
the substrate core and exposing a portion of the conductive layer
at the distal portion; and a sensing layer, in communication with
the active region, configured for at least one of amperometric
sensing and potentiometric sensing of the analyte.
2. The sensor of claim 1, wherein the conductive layer comprises a
titanium-platinum composition.
3. The sensor of claim 2, wherein the insulating layer comprises a
chemical vapor deposited oxide.
4. The sensor of claim 3, further comprising a metal contact pad
coupled to the substrate.
5. The sensor of claim 1, wherein the sensing layer comprises
distributions of at least two of: tyramine, glucose oxidase, a
phenylenediamine component, and an amine-decorated polymer
component.
6. The sensor of claim 5, further comprising a selective layer,
having a distribution of molecules that interact with the analyte,
coupled to the sensing layer.
7. The sensor of claim 1, further comprising an adhesion layer,
superficial to the conductive layer and the sensing layer and
isolated to the tip region of the filament.
8. The sensor of claim 7, wherein the adhesion layer comprises at
least one of urethane and polyvinyl alcohol.
9. The sensor of claim 1, further including an intermediate active
layer, superficial to the conductive layer and deeper than the
sensing layer, relative to an exterior surface of the filament,
including a material for facilitating signal transduction upon
detection of the analyte.
10. The sensor of claim 1, wherein the columnar protrusion has a
rectangular cross section across a transverse plane defined in
relation to a longitudinal axis of the columnar protrusion.
11. A sensor for sensing analytes present in a body fluid of a
user, the sensor comprising: a substrate; and an array of
filaments, each filament in the array of filaments comprising: a
substrate core comprising: a base end, coupled to the substrate,
and a distal portion operable to provide access to the body fluid
of the user during operation of the sensor; a conductive layer,
isolated to the distal portion of the substrate core and away from
the base end as an active region operable to transmit electronic
signals generated upon detection of an analyte within the body
fluid; and an insulating layer surrounding the substrate core and
exposing the active region.
12. The sensor of claim 11, wherein, for each of the array of
filaments, the conductive layer comprises a titanium-platinum
composition and the insulating layer comprises a chemical vapor
deposited oxide.
13. The sensor of claim 11, further comprising a metal contact pad
coupled to the substrate.
14. The sensor of claim 11, wherein each filament in the array of
filaments further comprises: a sensing layer, in communication with
the active region, configured for at least one of amperometric
sensing and potentiometric sensing of the analyte.
15. The sensor of claim 14, wherein the sensing layer comprises a
distribution of at least one of: a phenylenediamine component and
an amine-decorated polymer component.
16. The sensor of claim 15, wherein each of the array of filaments
further comprises an adhesion layer configured to facilitate
coupling between at least two of the substrate core, the conductive
layer, the insulating layer, and the sensing layer, wherein the
adhesion layer comprises polyvinyl alcohol.
17. The sensor of claim 14, wherein each of the array of filaments
further comprises a selective coating, having a distribution of
molecules that interact with the analyte, superficial to the
sensing layer.
18. The sensor of claim 11, wherein the selective coating comprises
polyvinyl alcohol with a distribution of glucose oxidase.
19. The sensor of claim 11, wherein, for each of the array of
filaments, the substrate core has a rectangular cross section, the
distal portion is pyramidal, the conductive layer is isolated to
the tip region and isolated away from the base end.
20. The sensor of claim 19, wherein the array of filaments has a
density of less than 100 filaments per cm.sup.2 of the substrate.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/876,692, filed 6 Oct. 2015, which is a
continuation of U.S. patent application Ser. No. 14/211,404, filed
14 Mar. 2014, which claims the benefit of U.S. Provisional
Application Ser. No. 61/905,583, filed on 18 Nov. 2013 and U.S.
Provisional Application Ser. No. 61/781,754, filed on 14 Mar. 2013,
which are all incorporated herein in their entirety by this
reference.
TECHNICAL FIELD
[0002] This invention relates generally to the medical device
field, and more specifically to a new and useful on-body
microsensor for biomonitoring.
BACKGROUND
[0003] Biomonitoring devices are commonly used, particularly by
health-conscious individuals and individuals diagnosed with
ailments, to monitor body chemistry. Conventional biomonitoring
devices typically include analysis and display elements. Such
biomonitoring devices perform the tasks of determining one or more
vital signs characterizing a physiological state of a user, and
provide information regarding the user's physiological state to the
user. In variations, biomonitoring devices can determine an analyte
level present in a user's body, and provide information regarding
the analyte level to the user; however, these current biomonitoring
devices typically convey information to users that is limited in
detail, intermittent, and prompted by the command of the user. Such
biomonitoring devices, including blood glucose meters, are also
inappropriate for many applications outside of intermittent use,
due to design and manufacture considerations. Additionally current
devices are configured to analyze one or a limited number of
analytes contributing to overall body chemistry, due to limitations
of sensors used in current biomonitoring devices.
[0004] There is thus a need in the medical device field to create a
new and useful on-body microsensor for biomonitoring. This
invention provides such a new and useful microsensor.
BRIEF DESCRIPTION OF THE FIGURES
[0005] FIG. 1A depicts an embodiment of a microsensor for
biomonitoring;
[0006] FIG. 1B depicts an embodiment of an array of filaments, and
a microsensor coupled to an electronics module;
[0007] FIG. 2A depicts an embodiment of a filament for
biomonitoring;
[0008] FIG. 2B depicts another embodiment of a filament for
biomonitoring;
[0009] FIGS. 2C and 2D depict examples of filaments for
biomonitoring;
[0010] FIG. 2E depicts an example of a filament, comprising an
adhesion layer, for biomonitoring;
[0011] FIG. 2F depicts an example of a filament, comprising a
temporary functional layer, for biomonitoring;
[0012] FIGS. 3A-3H depict embodiments of filament geometries;
[0013] FIG. 4 depicts an embodiment of a manufacturing method for
an on-body microsensor for biomonitoring;
[0014] FIGS. 5A-5C depict embodiments of a portion of a
manufacturing method for an on-body microsensor for
biomonitoring;
[0015] FIGS. 6A and 6B depict variations of forming a filament
substrate;
[0016] FIGS. 7A-7D depict variations of defining an active region
and a non-active region of the filament with an insulating
layer;
[0017] FIGS. 8A-8E depict variations of a portion of an embodiment
of a method for an on-body microsensor for biomonitoring; and
[0018] FIG. 9 depicts a portion of an embodiment of a method for an
on-body microsensor for biomonitoring.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0019] The following description of the preferred embodiments of
the invention is not intended to limit the invention to these
preferred embodiments, but rather to enable any person skilled in
the art to make and use this invention.
1. Microsensor
[0020] As shown in FIGS. 1A, 2A, and 2B, an embodiment of a
microsensor 100 comprises an array of filaments 110, wherein each
filament 120 of the array of filaments 110 comprises a substrate
130 and a conductive layer 140 configured to facilitate analyte
detection. Alternatively, the substrate 130 itself can be
conductive with no additional conductive layer 140. Each filament
120 of the array of filaments 110 can further comprise an
insulating layer 150 configured to isolate regions for analyte
detection, a sensing layer 160 configured to enable transduction of
an ionic concentration to an electronic voltage, and a selective
coating 170 configured to facilitate detection of specific target
analytes/ions. Any filament 120 of the array of filaments 110 can
further comprise an adhesion coating 180 configured to maintain
contact between layers, coatings, and/or substrates of the filament
120, and a temporary functional layer 190 configured to facilitate
penetration of a filament into the body. The microsensor 100 and
the array of filaments 110 thus function to penetrate a user's skin
in order to sense at least one target analyte characterizing the
user's body chemistry. Preferably, the microsensor 100 is
configured to be worn by a user, such that continuous or
semi-continuous monitoring of the user's body chemistry is enabled;
however, the microsensor 100 can alternatively be used
intermittently to sense analytes characterizing the user's body
chemistry. Preferably, the microsensor 100 is configured to
penetrate the user's stratum corneum (e.g., an outer skin layer) in
order to sense analytes characterizing the user's body chemistry in
the user's interstitial (extracellular) fluid; however, the
microsensor 100 can alternatively be configured to penetrate deeper
layers of a user's skin in order to sense analytes within any
appropriate bodily fluid of the user, such as the user's blood. The
microsensor 100 can be configured to sense analytes/ions
characterizing a user's body chemistry using a potentiometric
measurement (e.g., for analytes including potassium, sodium
calcium, alcohol, cortisol, hormones, etc.), using an amperometric
measurement (e.g., for analytes including glucose, lactic acid,
creatinine, etc.), using a conductometric measurement, or using any
other suitable measurement.
[0021] As shown in FIG. 1B, the microsensor 100 can also be coupled
to an electronics module 115, such that sensed analytes result in a
signal (e.g., voltage, current, resistance, capacitance, impedance,
gravimetric, etc.) detectable by the electronics module 115;
however, analyte sensing can comprise any other appropriate
mechanism using the microsensor 100. In an embodiment wherein the
microsensor 100 is coupled with an electronics module 115, the
microsensor 100 can also be integrated with the electronics module
115, in variations wherein the electronics module 115 is
characterized by semiconductor architecture. In a first variation,
the microsensor 100 is coupled to the semiconductor architecture of
the electronics module 115 (e.g., the microsensor 100 is coupled to
an integrated circuit comprising the electronics module 115), in a
second variation, the microsensor 100 is more closely integrated
into the semiconductor architecture of the electronics module 115
(e.g., there is closer integration between the microsensor 100 and
an integrated circuit including the electronics module 115), and in
a third variation, the microsensor 100 and the electronics module
115 are constructed in a system-on-a-chip fashion (e.g., all
components are integrated into a single chip). As such, in some
variations, filaments 120 the array of filaments 110 of the
microsensor 100 can be directly or indirectly integrated with
electronics components, such that preprocessing of a signal from
the microsensor 100 can be performed using the electronics
components (e.g., of the filaments 120, of the electronics module
115) prior to or after transmitting signals to the electronics
module 115 (e.g., to an analog to digital converter). The
electronics components can be coupled to a filament substrate, or
otherwise integrated with the filaments in any suitable fashion
(e.g., wired, using a contact pad, etc.). Alternatively, the
electronics components can be fully integrated into the electronics
module 115 and configured to communicate with the microsensor 100,
or the electronics components can be split between the microsensor
and the electronics module 115. The microsensor 100 can, however,
comprise any other suitable architecture or configuration.
[0022] The microsensor 100 preferably senses analyte parameters
using the array of filaments 110, such that absolute values of
specific analyte parameters can be detected and analyzed. The
microsensor 100 can additionally or alternatively be configured to
sense analyte parameters using the array of filaments 110, such
that changes in values characterizing specific analyte parameters
or derivatives thereof (e.g., trends in values of a parameter,
slopes of curves characterizing a trend in a parameter vs. another
parameter, areas under curves characterizing a trend, a duration of
time spent within a certain parameter range, etc.) can be detected
and analyzed. In one variation, sensing by the microsensor 100 is
achieved at discrete time points (e.g., every minute or every
hour), and in another variation, sensing by the microsensor 100 is
achieved substantially continuously. Furthermore, sensing can be
achieved continuously, with signal transmission performed in a
discrete or non-discrete manner (e.g., prior to or subsequent to
processing of a signal). In one specific example for blood
chemistry analysis, the array of filaments 110 of the microsensor
100 is configured to sense at least one of electrolytes, glucose,
bicarbonate, creatinine, blood urea nitrogen (BUN), sodium, and
potassium of a user's body chemistry. In another specific example,
the array of filaments 110 of the microsensor 100 is configured to
sense at least one of biomarkers, cell count, hormone levels,
alcohol content, gases, drug concentrations/metabolism, pH and
analytes within a user's body fluid.
1.1 Microsensor--Array of Filaments
[0023] The array of filaments 110 functions to interface directly
with a user in a transdermal manner in order to sense at least one
analyte characterizing the user's body chemistry. The array of
filaments can be an array of fibers, an array of pillars, an array
of microneedles, and/or any other suitable array configured to
facilitate analyte detection in a user. The array of filaments 110
is preferably arranged in a uniform pattern with a specified
density optimized to effectively penetrate a user's skin and
provide an appropriate signal, while minimizing pain to the user.
However, the array of filaments 110 can additionally or
alternatively be coupled to the user in any other suitable manner
(e.g., using an adhesive, using a coupling band/strap, etc.).
Additionally, the array of filaments 110 can be arranged in a
manner to optimize coupling to the user, such that the microsensor
100 firmly couples to the user over the lifetime usage of the
microsensor 100. For example, the filaments 120 can comprise
several pieces and/or be attached to a flexible base to allow the
array of filaments 110 to conform to a user's body. In one
variation, the array of filaments 110 is arranged in a rectangular
pattern, and in another variation, the array of filaments 110 is
arranged in a circular or ellipsoid pattern. However, in other
variations, the array of filaments 110 can be arranged in any other
suitable manner (e.g., a random arrangment). The array of filaments
110 can also be configured to facilitate coupling to a user, by
comprising filaments of different lengths or geometries. Having
filaments 120 of different lengths can additionally or
alternatively function to allow measurement of different
ions/analytes at different depths of penetration (e.g., a filament
with a first length may sense one analyte at a first depth, and a
filament with a second length may sense another analyte at a second
depth). The array of filaments 110 can also comprise filaments 120
of different geometries (e.g., height, diameter) to facilitate
sensing of analytes/ions at lower or higher concentrations. In one
specific example, the array of filaments 110 is arranged at a
density of 100 filaments per square centimeter and each filament
120 in the array of filaments 110 has a length of 250-350 microns,
which allows appropriate levels of detection, coupling to a user,
and comfort experienced by the user. In variations of the specific
example, a filament 120 in the array of filaments 120 can have a
length from 0-1000 m., or more specifically, a length from 150-500
.mu.m.
[0024] Each filament 120 in the array of filaments 110 preferably
functions to sense a single analyte; however, each filament 120 in
the array of filaments 110 can additionally be configured to sense
more than one analyte. Furthermore, the array of filaments 110 can
be further configured, such that a subarray of the array of
filaments 110 functions as a single sensor configured to sense a
particular analyte or biomarker. As shown in FIG. 1B, multiple
subarrays of the array of filaments 110 may then be configured to
sense different analytes/biomarkers, or the same analyte/biomarker.
Furthermore, a subarray or a single filament 120 of the array of
filaments 110 can be configured as a ground region of the
microsensor 100, such that signals generated by the microsensor 100
in response to analyte detection can be normalized by the signals
generated by the subarray or single filament 120 serving as a
ground region. Preferably, all subarrays of the array of filaments
110 are substantially equal in size and density; however, each
subarray of the array of filaments 110 can alternatively be
optimized to maximize signal generation and detection in response
to a specific analyte. In an example, analytes that are known to
have a lower concentration within a user's body fluid (e.g.,
interstitial fluid, blood) can correspond to a larger subarray of
the array of filaments 110. In another example, analytes that are
known to have a lower concentration within a user's body fluid can
correspond to a smaller subarray of the array of filaments 110. In
one extreme example, an entire array of filaments can be configured
to sense a single analyte, such that the microsensor 100 is
configured to sense and detect only one analyte.
[0025] In other variations, a subarray of the array of filaments
117 can also be used to detect other physiologically relevant
parameters, including one or more of: electrophysiological signals
(e.g., electrocardiogram, electroencephalogram), body temperature,
respiration, heart rate, heart rate variability, galvanic skin
response, skin impedance change (e.g., to measure hydration state
or inflammatory response), and any other suitable biometric
parameter. In these other variations, the subarray would be
dedicated to measuring these physiologically relevant parameters,
which could be combined with analyte/ion parameter measurements in
order to provide meaningful information to a user. As an example,
the simultaneous measurement of potassium levels and
electrocardiogram measurements, enabled by subarrays of the array
of filaments 117, may provide a more complete diagnosis of
cardiovascular problems or events than either measurement by
itself.
1.2 Microsensor--Filament
[0026] As shown in FIG. 2A, each filament 120 of the array of
filaments 110 comprises a substrate 130 and a conductive layer 140
configured to facilitate analyte detection. Each filament 120 of
the array of filaments 110 can further comprise an insulating layer
150 configured to isolate regions for analyte detection, a sensing
layer 160 configured to enable transduction of an ionic
concentration to an electronic voltage, and a selective coating 170
configured to facilitate detection of specific target analytes. As
shown in FIG. 2E, each filament can further comprise an adhesion
coating 180 configured to maintain contact between layers,
coatings, and/or substrates of the filament 120, and/or a temporary
functional layer 190, as shown in FIG. 2F, configured to facilitate
penetration of a filament 120 into the body. A filament 120 thus
functions to directly penetrate a user's skin, and to sense
specific target analytes/ions characterizing the user's body
chemistry.
[0027] The substrate 130 functions to provide a core or base
structure upon which other layers or coatings can be applied, in
order to facilitate processing of each filament 120 for specific
functionalities. As such, the material of which the substrate 130
is composed can be processed to form at least one protrusion as a
substrate core for a filament 120, including a base end coupled to
the substrate 130 bulk and a tip at the distal end of the substrate
core, that facilitates access to a body fluid of the user.
Alternatively, the substrate 130 can be coupled to a protrusion
(e.g., as a piece separate from the substrate) or a protrusion can
be grown from a surface of the substrate 130 in any other suitable
manner. Preferably, the material of the substrate 130 is
processable to form an array of protrusions as substrate cores for
the array of filaments 110; however, the material of the substrate
130 can alternatively be processable in any other suitable manner
to form any other suitable filament structure. Preferably, the
substrate 130 has a uniform composition; however, the substrate 130
can alternatively have a non-uniform composition comprising regions
or layers configured to facilitate processing of subsequent
functional layer/coating additions. The substrate 130 can be
composed of a semiconducting material (e.g., silicon, quartz,
gallium arsenide), a conducting material (e.g., gold, steel,
platinum, nickel, silver, polymer, etc.), and/or an insulating or
non-conductive material (e.g., glass, ceramic, polymer, etc.). In
some variations, the substrate 130 can comprise a combination of
materials (e.g., as in a composite, as in an alloy). Furthermore,
in variations wherein the substrate 130 is non-conductive, a fluid
path defined at the substrate 130 (e.g., a fluid channel, a groove,
a hollow region, an outer region, etc.) and coupled to a conductive
layer 140 (e.g., a conductive base region, a conductive core, a
conductive outer layer) can enable signal transmission upon
detection of an analyte/analyte concentration. In a specific
example, the substrate 130 is composed of P-type, boron-doped,
<100> orientation silicon with a resistivity of 0.005-0.01
ohm-cm, a thickness from 500-1500 .mu.m, a total thickness
variation (TTV) of <10 .mu.m, with a first surface side polish.
In variations of the specific example, the substrate 130 can be
composed of silicon with any other suitable type, doping, miller
index orientation, resistivity, thickness, TTV, and/or polish.
Furthermore, the substrate 130 can be processed using semiconductor
processing methods, machining methods, manufacturing processes
suited to a ductile substrate material, and/or manufacturing
methods suited to a brittle material.
[0028] The conductive layer 140 functions to provide a conductive
"active" region to facilitate signal transmission upon detection of
an analyte by a filament 120. The conductive layer 140 can comprise
a layer of a single material, or can alternatively comprise
multiple materials (e.g., multiple layers of one or more
materials). In variations, the conductive layer 140 can include any
one or more of: a platinum-based material, an iridium-based
material, a tungsten-based material, a titanium-based material, a
gold-based material, a nickel-based material, and any other
suitable conductive or semiconducting material (e.g., silicon,
doped silicon). Furthermore, the layer(s) of the conductive layer
140 can be defined by any suitable thickness that allows signal
transmission upon detection of an analyte by the filament 120. In a
first specific example, the conductive layer 140 includes a 1000
.ANG. thick platinum layer, a 1000 .ANG. thick iridium layer, a
1000 .ANG. thick tungsten layer, and a 100 .ANG. thick titanium
nitride layer. In a second specific example, the conductive layer
140 includes a 1000 .ANG. thick platinum layer and a 100 .ANG.
thick titanium layer. In a third specific example, the conductive
layer 140 includes a 1000 .ANG. thick platinum layer and a 100
.ANG. thick titanium nitride layer. In a fourth specific example,
the conductive layer 140 includes a 1000 .ANG. thick iridium layer
and a 100 .ANG. thick titanium nitride layer. In a fifth specific
example, the conductive layer 140 includes a 1000 .ANG. thick
tungsten layer. In a sixth specific example, the conductive layer
140 includes one or more of: nickel, gold, and platinum (e.g.,
deposited by electroplating). Preferably, the conductive layer 140
only covers a portion of the substrate 130 (e.g., a substrate core)
contacting the user's body fluids, thus forming an "active region"
of the filament 120, and in one variation, covers a tip region of
each filament 120 (e.g., a tip of a substrate core); however, the
conductive layer 140 can alternatively cover the entire surface of
the substrate 130 contacting a user's body fluids. In variations
wherein the substrate 130 is conductive, the filament 120 can
altogether omit the conductive layer 140. Furthermore, in
variations wherein the substrate 130 is non-conductive, a fluid
path defined at the substrate 130 (e.g., a fluid channel, a groove,
a hollow region, an outer region, etc.) and coupled to a conductive
layer 140 (e.g., a conductive base region, a conductive core, a
conductive outer layer) can enable signal transmission upon
detection of an analyte/analyte concentration, as described
above.
[0029] The insulating layer 150 functions to form an insulating
region of a filament 120, and is configured to provide a
"non-active" region of the filament 120. Additionally, the
insulating layer 150 functions to define and/or isolate an "active"
region of the filament 120. As such, the insulating layer 150
preferably leaves at least a portion of the conductive layer 140
exposed to define the active region of the filament 120. In one
variation, the insulating layer 150 ensheathes the substrate core
of each filament 120 in the array of filaments, and can
additionally or alternatively cover all exposed regions of the
substrate 130 to isolate areas of signal transmission. The
insulating layer 150 preferably includes an oxide layer that is
grown at desired surfaces of the substrate (e.g., to a thickness of
0.1-10 .mu.m), thereby forming the insulating layer. However, the
insulating layer 150 can additionally or alternatively include any
other suitable material that is not removable during removal of
sacrificial layers used during processing of the array of filaments
110. As such, in other variations, the insulating layer 150 can be
composed of any one or more of: an insulating polymer (e.g.,
polyimide, cyanate ester, polyurethane, silicone) that is chemical
and/or heat resistant, an oxide, a carbide, a nitride (e.g., of
silicon, of titanium), and any other suitable insulating material.
Preferably, the insulating layer 150 only covers a portion of the
substrate contacting the user's body fluids, thus defining an
"active region" of the filament 120 and a "non-active" region of
the filament 120. Alternatively, the filament 120 can altogether
omit the insulating layer 150.
[0030] The sensing layer 160 functions to enable transduction of an
ionic concentration to an electronic voltage, to enable measurement
of analyte/ion concentrations characterizing body chemistry. The
sensing layer 160 can also function to prevent unwanted signal
artifacts due to oxygen fluxes in a user's body fluids.
Furthermore, the sensing layer 160 can also enable transduction of
a molecular species concentration through a current, capacitance,
or resistance change. Preferably, the sensing layer is a conductive
material with reversible redox reaction behavior, such that
detection of increased ion concentrations followed by decreased ion
concentrations (or visa versa) can be enabled by the sensing layer
160. Additionally, the sensing layer 160 is preferably an
appropriately bio-safe, anti-inflammatory, and anti-microbial
material. The sensing layer 160 can be a polymer, such as
polypyrrole or polyaniline, which undergoes a reversible redox
reaction characterized by the following generic equation:
P.sup.(ox)+e-P.sup.(red). The sensing layer 160 can additionally or
alternatively be composed of any appropriate conductive material
(e.g., sulfur-containing polythiophenes, silver chloride, etc.)
that has reversible redox reaction behavior. For example, silver
chloride undergoes a reversible redox reaction characterized by the
following equation: AgCl+e-Ag(s).sup.++Cl.sup.-. In either example
redox reaction equation, electron (e-) generation results in
measurable signals corresponding to detected ion concentrations for
analyte detection, and further, the sensing layer 160 serves as a
reference electrode for ion concentration measurements based upon a
detected voltage change across a selective coating 170 coupled to
the sensing layer 160. However, in other variations, the sensing
layer 160 may not comprise a material with reversible redox
reaction behavior, and other variations can further comprise a
controlled ion coating (e.g., poly-hydroxyl ethyl methacrylate
prepared with potassium chloride) that functions to form a portion
of a reference electrode for ion concentration measurements.
Additionally or alternatively, the sensing layer 160 can include
molecules (e.g., glucose oxidase, phenylenediamine, gluteraldehyde,
lysine, tyramine, trehalose, lipids, surfactants, etc.) that
facilitate analyte detection. In one example, the sensing layer 160
includes electropolymerized phenylenediamene, tyramine, glucose
oxidase, and poly-lysine to facilitate glucose sensing. The sensing
layer 160 is preferably uniform over an active region of a filament
120 defined by the conductive layer 140 and the insulating layer
150; however, the sensing layer 160 can alternatively
non-discriminately coat the surface of the filament 120, and/or can
be a non-uniform coating. The sensing layer 160 can be maintained
at a viable state by packaging the microsensor 100 in a hydrated
state; however, the sensing layer 160 can be alternatively be
configured to equilibrate within a short time period (e.g., less
than one hour) upon coupling of the array of filaments 110 to a
user. Alternative variations of the filament may altogether omit
the sensing layer 160.
[0031] The selective coating 170 functions to facilitate sensing of
specific target analytes. The selective coating 170 preferably
facilitates ion-selective reactions that generate signals
reflective of ion concentration; however, the selective coating 170
can additionally or alternatively facilitate enzyme reactions that
generate changes in signals (e.g., current) due to binding of
complementary molecules to target analytes/ions. The selective
coating 170 is preferably anti-microbial and anti-inflammatory, and
can additionally or alternatively include any other features that
encourage biocompatibility during use by a user. Preferably, the
selective coating 170 comprises at least one complementary molecule
171 (e.g., ionophore, protein, peptide, amino acid, etc.) to a
target analyte/ion distributed within a polymer matrix 172, as
shown in FIG. 2A. Preferably, the complementary molecule 171 is
evenly dispersed throughout the polymer matrix 172; however, the
complementary molecule 171 can alternatively be localized within
regions of the polymer matrix 172 in a heterogeneous manner. In
examples, the complementary molecule is valinomycin/potassium
tetrakis for potassium sensing,
4-tert-Butylcalix[4]arene-tetraacetic acid tetraethyl ester for
sodium sensing, (-)-(R,R)-N,N'-Bis-[11-(ethoxycarbonyl)
undecyl]-N,N',4,5-tetramethyl-3,6-dioxaoctane-diamide, Diethyl
N,N'-[(4R,5R)-4,5-dimethyl-1,8-dioxo-3,6-dioxaoctamethylene] bis
(12-methylaminododecanoate) for calcium sensing, and
meso-Tetraphenylporphyrin manganese(III)-chloride complex for
chloride sensing, according to ion-selective reactions. In an
example, the polymer matrix 172 is composed of polyvinyl chloride
(PVC) with a plasticizer to affect flexibility of the polymer
matrix; however, the polymer matrix 172 can additionally or
alternatively be composed of any other suitable polymer (e.g.,
polyethylene, polytetrafluoroethylene, urethane, parylene, nafion,
polyvinyl chloride, polyvinyl alcohol, polyvinyl butyral,
polydimethylsiloxane, fluorinated polymers, cellulose acetate,
etc.) or non-polymer (e.g., oxide, nitride, carbide, etc.)
configured to contain a distribution of complementary molecules.
Additionally, the selective coating 170 may not comprise a
plasticizer. The selective coating 170 is preferably defined by a
thickness that characterizes a rate at which complementary
molecules bind to target analytes (e.g., diffusion rate), and that
also characterizes the amount (e.g., concentration or total amount)
of complementary molecules within the selective coating 170.
Additionally, the polymer matrix 172 can contain additives and can
additionally or alternatively be processed (e.g., with polar
functional groups) to improve its adhesion to the filament 120 and
to prevent delamination as the filament 120 is inserted into a
user's skin. In examples, additives of the polymer matrix 172 can
include amino-silicanes, polyhydroxy-ether imides, butylated
silica, and heterogeneous oxidizers.
[0032] In other variations, the selective coating 170 of the
filament 120 can additionally or alternatively function to enable
amperometric detection of molecules (e.g., glucose, creatinine)
using immobilized enzymes. In these variations, the selective
coating 170 can be replaced by or may further comprise a layer of
immobilized enzyme (e.g., glucose oxidase for glucose, creatine
amidinohydrolase for creatinine) that functions to catalyze a
reaction of the analyte to produce a mediator species (e.g.,
hydrogen peroxide), wherein the concentration of the mediatior
species can be amperometrically detected via oxidation or reduction
at a surface of the conductive layer 140 or the sensing layer 160.
In one example, glucose is oxidized by glucose oxidase to generate
hydrogen peroxide. The generated hydrogen peroxide is then
hydrolyzed by a conducting surface (e.g., a platinum conducting
layer) while it is held at an electric potential. In a variation of
this example, the conducting surface may alternatively not be held
at an electric potential, for instance, in cases wherein molecular
or other species (e.g., iron hexacyanoferrate) serve as a layer of
transduction. Furthermore, in other variations of this example,
other oxidases (e.g. alcohol oxidase, D- and L-amino acid oxidases,
cholesterol oxidase, galactose oxidase, urate oxidase, etc.) can be
used in a similar manner for the analysis of their complements.
[0033] In variations of the sensing layer including a layer of
immobilized enzymes, the layer of immobilized enzymes can be
covered by one or more membranes, which functions to control the
diffusion rate and/or concentrations of analyte, mediator species
(e.g., hydrogen peroxide, ferrocene), or interfering species (e.g.,
uric acid, lactic acid, ascorbic acid, acetaminophen, oxygen). The
membrane(s) can also function to provide mechanical stability. In
examples, the membrane(s) can include any one or more of:
polyurethanes, nafion, cellulose acetate, polyvinyl alcohol,
polyvinyl chloride, polydimethylsiloxane, parylene, polyvinyl
butyrate and any other suitable membrane material.
[0034] As shown in FIG. 2E, any filament 120 of the array of
filaments 110 can further comprise an adhesion coating 180, which
functions to maintain contact between layers, coatings, and/or
substrates of the filament 120. The adhesion coating 180 can
further function to bond the layers, coatings, and/or substrates,
and can prevent delamination between the layers, coatings, and/or
substrates. The adhesion coating 180 is preferably an appropriately
bio-safe, anti-inflammatory, and anti-microbial material, and
preferably maintains contact between layers, coatings, and/or
substrates of the filament 120 over the lifetime usage of the
microsensor 100. In examples, the adhesion coating 180 is composed
of any one or more of: a polyurethane, nafion, cellulose acetate,
polyvinyl alcohol, polyvinyl butyrate, polyvinyl chloride,
polydimethylsiloxane, paralyene, any material used in variations of
the selective coating 170, and any other suitable adhesion
material. However, in variations, a filament 120 of the microsensor
100 can alternatively not comprise an adhesion coating 180.
Alternatively, layers, coatings, and/or substrates of the filament
can be treated (e.g., heat treated, ultraviolet radiation treated,
chemically bonded, etc.) and/or processed such that appropriate
contact is maintained, even without an adhesion coating 180.
[0035] As shown in FIG. 2F, any filament 120 can further comprise a
temporary functional layer 190, which functions to facilitate
penetration of a filament 120 into the body. After the filament 120
has penetrated the body, the temporary functional layer 190 is
preferably configured to dissolve or be absorbed by the body,
leaving other portions of the filament 120 to operate to detect
target analytes/ions characterizing a user's body chemistry. The
temporary functional layer 190 can be configured, such that the
sensing layer 160 is at an appropriate depth for detection (e.g.,
has access to interstitial fluid below the user's stratum corneum),
once the temporary functional layer 190 has penetrated the user's
body. The temporary functional layer 190 is preferably composed of
an inert, bioabsorbable material that is porous; however, the
temporary functional layer 190 can alternatively not be porous or
bioabsorbable. In some variations, the temporary functional layer
190 can be configured to release an initial ion concentration with
a known release profile (e.g., spiked or continuous release) in
order to calibrate the microsensor 100. In specific examples, the
temporary functional layer 190 can include a nitride material
(e.g., 1000-2500 .ANG. thick nitride), an oxide material, a carbide
material, a salt, a sugar, a polymer (e.g., polyethylene glycol),
and/or any other suitable material that does not deteriorate during
subsequent processing steps. Other variations of the filament can
further comprise any other suitable temporary functional layer 190
providing any other suitable function.
[0036] Any filament 120 of the microsensor 100 can further comprise
any other appropriate functional layer or coating. In variations, a
filament 120 can comprise layers or coatings that perform any one
or more of the following functions: suppress or prevent an
inflammatory response (e.g., by comprising a surface treatment or
an anti-inflammatory agent), prevent bio-rejection, prevent
encapsulation (e.g., by comprising a bio-inert substance, such as
pyrolytic carbon), enhance target analyte/ion detection, and
provide any other suitable anti-failure mechanism for the array of
filaments 110. In one such variation, a filament 120 of the
microsensor 100 can include a biocompatible layer 185 appropriately
situated (e.g., situated deeper than a temporary functional layer
190, situated superficial to an adhesion layer, etc.) to enhance
biocompatibility of the filament 120. In examples, the
biocompatible layer 185 can include a polymer (e.g., urethane,
parylene, teflon, fluorinated polymer, etc.) or any other suitable
biocompatible material. In another variation, a filament 120 of the
microsensor 100 can additionally or alternatively include an
intermediate protective layer 166 appropriately situated (e.g.,
situated deeper than a selective layer 170, etc.), which functions
as an optional layer to provide intermediate protection and/or
block transport of undesired species. In examples, the intermediate
protective layer can include a polymer (e.g., teflon, chlorinated
polymer, nafion, polyethylene glycol, etc.) and can include
functional compounds (e.g., lipids, charged chemical species that
block transport of charged species, etc.) configured to provide a
protective barrier. In another variation, a filament 120 of the
microsensor 100 can additionally or alternatively include a
stabilizing layer 163 appropriately situated (e.g., situated deeper
than an intermediate protective layer 166, situated deeper than a
selective layer 170, situated superficial to a sensing layer 160,
etc.), which functions to stabilize the sensing layer 160. In one
example, the stabilizing layer 163 can include a polymer (e.g.,
electropolymerized phenylenediamine) acting to stabilize a
glucose-oxidase sensing layer 160. In another variation, a filament
120 of the microsensor 100 can additionally or alternatively
include an intermediate selective layer 145 appropriately situated
(e.g., situated deeper than a sensing layer 160, situated
superficial to a conductive layer 140, etc.), which functions to
provide an additional selective layer. The intermediate selective
layer can include or be coupled to an immobilized complementary
molecule (e.g., glucose oxidase) to facilitate analyte detection.
In an example, the intermediate selective layer 145 includes a
polymer (e.g., electropolymerized phenylenediamine) and is situated
superficial to a conductive layer 140; however, in variations of
the example, the intermediate selective layer 145 can include any
other suitable selective material and can be situated relative to
other layers in any other suitable manner. In another variation, a
filament 120 of the microsensor 100 can additionally or
alternatively include an intermediate active layer 143
appropriately situated (e.g., situated deeper than an intermediate
selective layer 145, situated deeper than a sensing layer 143,
situated superficial to a conductive layer 140, etc.), which
functions to facilitate transduction of a signal. As such, the
intermediate active layer 143 can facilitate transduction in
variations wherein the conductive layer 140 is not held at a given
potential, and/or can facilitate transduction in any other suitable
manner. In one example, the intermediate active layer 143 comprises
iron hexacyanoferrate (i.e., Prussian Blue) and in another example,
the intermediate active layer 143 comprises nano-Platinum; however,
the intermediate active layer 143 can additionally or alternatively
include any other suitable material.
[0037] In any of the above embodiments, variations, and examples,
any one or more of layers 185, 166, 163, 145, 143 can isolated to a
desired region of the filament 120, or can non-discriminately coat
an entire surface of the filament 120 at a given depth.
Furthermore, any filament 120 of the microsensor 100 can include
multiple instances of any layer or coating 140, 143, 145, 150, 160,
163, 166, 170, 180, 185, 190, can omit a layer or coating 140, 143,
145, 150, 160, 163, 166, 170, 180, 185, 190, and/or can include
layers or coatings arranged in any other suitable manner different
from the variations and examples described above and below. In one
such variation, a different configuration of layers can allow
selective passage of molecules having different properties (e.g.,
chemistries, size). However, any suitable configuration of a
filament 120 can be provided for any other suitable
application.
[0038] As shown in FIG. 3, each filament 120 of the array of
filaments 110 can have one of a variation of geometries. In a first
geometric variation a filament 120 can be solid, examples of which
are shown in FIGS. 3B and 3D-3G. In a first example of the solid
filament 120, the solid filament 120 can have a profile tapering
continuously to at least one point (e.g., pyramid or conical shaped
with one or more pointed tips), and can have straight or curved
edges, as shown in FIGS. 3B, 3D, and 3G. In variations, the
point(s) of the filament 120 can be defined by any suitable number
of faces. In a second example of the solid filament 120, the solid
filament 120 can comprise two regions--a pointed tip region 121
configured to pierce a user's skin, and a blunt region 122 (e.g., a
columnar protrusion, a pillar), coupled to the pointed tip region,
as shown in FIG. 3E. The pointed tip region 121 can be configured
to be bioabsorbable, dissolve (e.g., using a degradable material)
or, in an extreme example, break off (e.g., using an engineered
stress concentration) and be expelled from a user's system after
the solid filament 120 has penetrated the user's skin; however, the
pointed tip region 121 can alternatively be configured to remain
attached to the solid filament 120 after the solid filament 120 has
penetrated the user's skin. In a third example of the solid
filament 120, the solid filament 120 can comprise two regions--a
barbed tip region 123 including a barb configured to penetrate a
user's skin and promote skin adherence, and a second region 122
coupled to the barbed tip region, as shown in FIG. 3F. In the third
example of the solid filament 120, the barbed tip region can be
configured to have one sharp protrusion for skin penetration, or
can alternatively be configured to have multiple sharp protrusions
for skin penetration.
[0039] In a second geometric variation, examples of which are shown
in FIGS. 3A, 3C, and 3H, a filament 120 can be hollow and comprise
a channel 125 within an interior region of the hollow filament 120.
In a first example of the hollow filament 120, the hollow filament
120 can have a profile tapering continuously to at least one point
(e.g., pyramid or conical shaped with one or more pointed tips),
and can have straight or curved edges. Furthermore, the point(s) of
the filament 120 can be defined by any suitable number of faces. In
the first example of the hollow filament 120, the hollow filament
120 can additionally be processed to have one or more channels 125
configured to facilitate sensing of an analyte characterize a
user's body chemistry. In the first example, a channel 125 of the
hollow filament 120 can be characterized by a uniform cross section
along the length of the channel 125, or can alternatively be
characterized by a non-uniform cross section along the length of
the channel 125. In a second example of a hollow filament 120, the
hollow filament 120 can be configured to receive a volume of the
user's body fluid into a sensing chamber to facilitate analyte
detection. In the second geometric variation, the hollow filament
120 can be composed of a metal or a semiconductor, or any
appropriate material to facilitate analyte sensing. In other
examples, the hollow filament 120 may implement a variation of any
of the solid filaments described above, but be processed to have at
least one channel 125 within an interior region of the hollow
filament 120. Each filament 120 in the array of filaments 110 can
include a combination of any of the above geometric variations, a
different variation of the above geometric variations, and
furthermore, the array of filaments 110 can comprise filaments
characterized by different geometric variations.
[0040] In a first specific example of a filament 120, as shown in
FIG. 2A, a solid filament 120 comprises a uniform silicon substrate
130 composed to P-type, boron-doped orientation <100> silicon
with a resistivity from 0.005-0.01 ohm-cm, a thickness of 500-1500
.mu.m, and a TIV less than 10 .mu.m, processed to define a
substrate core with a pointed tip region 121 formed by way of a
dicing saw, as described in Section 2 below. In the first specific
example, the filament comprises a conductive layer 140 of nickel,
coupled to the substrate 130 by electroplating, wherein the
conductive layer 140 is isolated to the pointed tip region 121 of
the substrate core, and to a face of the substrate 130 directly
opposing the face including the filament 120. In the first specific
example, the filament 120 further includes an insulating layer 150
of 1 .mu.m oxide, formed by thermal growth at 900-1050 C for 1-2
hours, as described in further detail below, wherein the insulating
layer 150 is formed at all exposed surfaces of the substrate 130
and defines an active region at the pointed tip region 121 of the
filament 120. In variations of the first specific example, the
conductive layer 140 can additionally or alternatively include one
or more of a gold-based material and a platinum-based material.
Furthermore, in the first specific example, the filament 120 can
include a conductive polymer (polypyrrole) coating as the sensing
layer 160 coupled to the conductive layer 140 at the pointed tip
region 121 of the filament 120, and a PVC selective coating 170
with complementary molecules 171 to target analytes coupled to the
sensing layer 160. In the first specific example, the solid
filament 120 is includes a rectangular prismatic columnar
protrusion, with a pointed tip region defined by four faces
tapering to a point, as shown in FIG. 5C, wherein two of the four
faces are orthogonal to each other and contiguous with two faces of
the rectangular prismatic columnar protrusion, and wherein the
other two faces are formed by way of a dicing saw with an angled
blade, as described further in Section 2 below.
[0041] In a second specific example of a filament 120 for glucose
sensing, which can be characterized as shown in FIG. 2B, a solid
filament 120 comprises a uniform silicon substrate 130 composed to
P-type, boron-doped orientation <100> silicon with a
resistivity from 0.005-0.01 ohm-cm, a thickness of 500-1500 .mu.m,
and a TIV less than 10 .mu.m, processed to define a substrate core
with a pointed tip region 121 formed by way of a dicing saw, as
described in Section 2 below. In the second specific example, the
filament comprises a conductive layer 140 of nickel, gold, and
platinum, coupled to the substrate 130 by electroplating, wherein
the conductive layer 140 is isolated to the pointed tip region 121
of the substrate core, and to a face of the substrate 130 directly
opposing the face including the filament 120. In the second
specific example, the filament 120 further includes an insulating
layer 150 of 0.1-10 .mu.m oxide, formed by thermal growth at
900-1050 C for 1-2 hours, as described in further detail below,
wherein the insulating layer 150 is formed at all exposed surfaces
of the substrate 130 and defines an active region including the
conductive layer 140 at the pointed tip region 121 of the filament
120. Furthermore, in the second specific example, the filament
includes electropolymerized phenylenediamene, tyramine, glucose
oxidase, and poly-lysine as the sensing layer 160 superficial to
the conductive layer 140 at the pointed tip region 121 of the
filament 120. In between the conductive layer 140 and the sensing
layer 160 at the pointed tip region 121, the second specific
example includes an intermediate selective layer 145 of
electropolymerized phenylenediamine polymer coupled to an
intermediate active layer 143 including iron hexacyanoferrate,
coupled directly to the conductive layer 140. Finally the second
specific example includes an intermediate protective layer 166 of
urethane, coupled to a stabilizing layer 163 of phenylenediamine
coupled to the sensing layer 160, surrounded by a PVC selective
coating 170 with complementary molecules 171 to target analytes
coupled to the sensing layer 160. In the second specific example,
the solid filament 120 is includes a rectangular prismatic columnar
protrusion, with a pointed tip region defined by four faces
tapering to a point, as shown in FIG. 5C, wherein two of the four
faces are orthogonal to each other and contiguous with two faces of
the rectangular prismatic columnar protrusion, and wherein the
other two faces are formed by way of a dicing saw with an angled
blade, as described further in Section 2 below.
[0042] In a third specific example of a filament 120, as shown in
FIG. 2C, a solid filament 120 comprises a uniform silicon substrate
130, a conductive layer 140 of platinum at the tip of the filament
120, an insulating layer 150 composed of polyimide isolating the
active region of the filament 120 to the tip of the filament, a
conductive polymer (polypyrrole) coating as the sensing layer 160,
and a PVC selective coating 170 with complementary molecules 171 to
target analytes. In the third specific example, the solid filament
120 is conical and has a profile tapering to a single sharp
point.
[0043] In a fourth specific example of a filament 120, as shown in
FIG. 2D, a hollow filament 120 comprises a uniform silicon
substrate 130, an external surface coated with an insulating layer
150 composed of polyimide, a conductive layer 140 of platinum
covering the surface of an interior channel 125, a conductive
polymer (polypyrrole) coating as a sensing layer 160 covering the
conductive layer 140 of platinum, and a selective PVC coating 170
covering the sensing layer 160. In the fourth specific example, the
hollow filament 120 is conical with a single cylindrical channel
125 passing through the axis of rotation of the conical filament
120.
[0044] Each filament 120 in the array of filaments 110 can also be
structured as any appropriate combination of the above variations
and/or examples of filament 120 composition and/or geometry, and/or
can be paired with a filament 120 serving as a reference electrode
configured to normalize a signal detected in response to analyte
sensing. Additionally, the array of filaments 110 can comprise
filaments characterized by different variations of filament
composition (e.g., composition of layers and/or coatings).
2. Manufacturing Method
[0045] As shown in FIG. 4, an embodiment of a manufacturing method
200 for the microsensor comprises forming a filament substrate
S210; applying a conductive layer to the filament substrate S220;
defining an active region and a non-active region of the filament
with an insulating layer S230; applying a sensing layer to at least
the conductive layer S240; and forming a selective layer S250,
coupled to the sensing layer, configured to target at least one
specific analyte characterizing body chemistry. The manufacturing
method 200 functions to form an array of filaments as part of a
microsensor for monitoring body chemistry. Preferably, the
manufacturing method 200 forms an array of substantially identical
filaments, wherein each filament in the array of filaments
comprises an active region for analyte detection, and a non-active
region comprising an insulating layer. Alternatively, the
manufacturing method 200 can form an array of substantially
non-identical filaments, with different portions of the array
having different functionalities and/or configurations.
2.1 Manufacturing Method--Substrate, Conductive Layer, and
Insulating Layer Processing
[0046] Block S210 recites forming a filament substrate, and
functions to form a core or base structure upon which other layers
or coatings can be applied, in order to facilitate processing of
each filament for specific functionalities. As shown in FIG. 5A, in
a first variation, Block S210 includes forming an array of
protrusions at a first surface of the substrate, by way of a dicing
saw S211. In variations of Block S211, forming an array of
protrusions can include forming an array of sharp protrusions
S211a, as shown in FIGS. 5B and 5C, by way of an angled blade
(e.g., a 60 degree blade, a 45 degree blade) of a dicing saw or
other saw characterized by a desired depth (e.g., 150-500 .mu.m),
configured to cut a desired number of facet-filament tips (e.g.,
2-facet tips, 4-facet tips, 6-facet tips, etc.) at a desired rate
(e.g., 1-10 mm/s). In block S211a, the dicing saw can be configured
to form the array of sharp protrusions through adjacent cuts in a
first direction, followed by adjacent cuts in a second direction
(e.g., orthogonal to the first direction), thereby forming a
2-dimensional array of sharp protrusions (i.e., sharp tips).
However, any suitable number of cuts in any suitable number of
directions can be used to form the array. Additionally or
alternatively, forming the array of protrusions in Block S211 can
including forming an array of columnar protrusions S211b at the
first surface of the substrate, by way of a non-angled blade of a
dicing saw of a desired depth (e.g., 25-500 .mu.m) and width (e.g.,
75-200 .mu.m) with a desired gap (e.g., 25-2000 .mu.m), configured
to cut a desired number of columnar protrusions at a desired rate
(e.g., 1-10 mm/s), wherein each columnar protrusion defines any
suitable cross sectional profile (e.g., polygonal, non-polygonal).
In block S211b, the dicing saw can be configured to form the array
of columnar protrusions through adjacent cuts in a first direction,
followed by adjacent cuts in a second direction (e.g., orthogonal
to the first direction), thereby forming a 2-dimensional array of
columnar protrusions. However, any suitable number of cuts in any
suitable number of directions can be used to form the array.
[0047] In variations of Block S211, Blocks S211a and S211b
preferably form protrusions with a sharp tip defined at the end of
each columnar protrusion in a one-to-one manner, as shown in FIG.
5B, wherein the sharp tip is substantially aligned with and
contiguous with a respective columnar protrusion: however, the
sharp tip(s) can be non-aligned with a respective columnar
protrusion, can be non-contiguous with a respective columnar
protrusion, and/or can be formed in a non-one-to-one manner with
the array of columnar protrusions. In some variations, a sharp tip
can comprise a pyramidal tip region defined by an irregular
pyramid, having a first pair of orthogonal faces, substantially
contiguous with two faces of the columnar protrusion, and a second
pair of orthogonal faces, angled relative to the first pair of
orthogonal faces, such that the tip is substantially aligned with a
vertex of the rectangular cross section of the columnar protrusion;
however, in other variations, the tip can be misaligned with a
vertex of the rectangular cross section of the columnar protrusion.
Furthermore, Blocks S211a and S211b can be performed in any
suitable order, in order to facilitate application of the
conductive layer to the filament substrate in variations of Block
S220 and/or defining an active region and a non-active region of
the filament with an insulating layer, in variations of Block S230.
In still further variations, alternatives to the first variation of
Block S210 can include forming the array of protrusions at the
first surface of the substrate by way of any other suitable method
of bulk material removal.
[0048] In the first variation, the substrate can be composed of a
semiconducting material (e.g., silicon, quartz, gallium arsenide),
a conducting material (e.g., gold, steel, platinum), and/or an
insulating material (e.g., glass, ceramic). In some variations, the
substrate 130 can comprise a combination of materials (e.g., as in
a composite, as in an alloy). In a specific example, the substrate
is composed of P-type, boron-doped, <100> orientation silicon
with a resistivity of 0.005-0.01 ohm-cm, a thickness from 500-1500
.mu.m, and a TIV of <10 .mu.m, with a first surface side polish.
In variations of the specific example, the substrate 130 can be
composed of silicon with any other suitable type, doping, miller
index orientation, resistivity, thickness, TTV, and/or polish.
[0049] As shown in FIG. 6A, in a second variation, Block S210
comprises creating a substrate, applying a photoresist to the
substrate, and etching the substrate to form the filament
substrate. The second variation of Block S210 preferably defines an
array of sharp protrusions, wherein each sharp protrusion has a
base end, coupled to the substrate, a sharp tip end, and a
rotational axis of symmetry defined between the base end and the
sharp tip end. In variations, each sharp protrusion can be defined
by an inwardly tapering profile, such that sharp protrusion has a
base end defined by a first width (or diameter), and widens from
the base end for at least a portion of the length of the sharp
protrusion. However, the second variation of Block S210 can include
forming protrusions, defined by any other suitable profile, at the
substrate. The second variation can comprise performing a Bosch
process, a deep-reactive ion etching (DRIE) process, any suitable
etch (e.g., a potassium hydroxide etch), or any other suitable
process to form the filament substrate. In a specific example of
the second variation, the substrate comprises a P++ and/or
silicon-doped silicon wafer with an oxide pad, a negative
photoresist is applied in a uniform pattern to the oxide pad, and
potassium hydroxide anisotropic etching is used to form the
filament substrate. In further detail regarding the specific
example, the substrate is composed of P-type, boron-doped,
<100> orientation silicon with a resistivity of 0.005-0.01
ohm-cm, a thickness from 500-1500 .mu.m, and a TTV of <10 .mu.m,
with a first surface side polish. In variations of the specific
example, the substrate 130 can be composed of silicon with any
other suitable type, doping, miller index orientation, resistivity,
thickness, TTV, and/or polish. In alternative examples of the
second variation, Block S210 can comprise using any appropriate
semiconductor substrate, applying a positive photoresist and/or a
negative photoresist to the semiconductor substrate, applying the
photoresist in a non-uniform pattern, and/or using any appropriate
etching method (e.g., anisotropic, isotropic) to form the filament
substrate.
[0050] In a third variation, as shown in FIG. 6B, Block S2100'
comprises etching an array into a ductile substrate and deforming
the array to form an array of protrusions, thus forming a filament
substrate. In a specific example of the third variation, an array
of v-shaped features is laser-etched into a ductile steel
substrate, and each v-shaped feature in the array of v-shaped
features is then deformed outward from the steel substrate by
90.degree. to form an array of v-shaped filament protrusions.
Alternative examples of the third variation can include etching the
array using any appropriate method (e.g., punching, die-cutting,
water cutting), etching any appropriate array feature (e.g., any
pointed feature), and deforming the array in any appropriate manner
(e.g., by any angular amount for each or all array features) to
form the array of protrusions. In alternative variations, the
filament substrate can be formed by any other suitable method
(e.g., molding, laser cutting, stamping, 3D printing, etc.).
[0051] Block S220 recites applying a conductive layer to the
filament substrate S220, and functions to form a conductive
"active" region to facilitate signal transmission upon detection of
an analyte by a filament of the microsensor. Preferably, Block S220
comprises coupling a conductive layer to the sharp tip of each
columnar protrusion in the array of columnar protrusions formed,
for example, in variations of Block S211a and S211b. In variations,
coupling the conductive layer can include electroplating a
conductive material or alloy of a conductive material (e.g.,
nickel, silver, iridium, tungsten, titanium, titanium nitride,
aluminum, cadmium, chromium, molybdenum, lead, gold, platinum,
etc.) to the sharp tip of each columnar protrusion. Block S220 can
additionally or alternatively comprise metalizing the filament
substrate by sputtering a layer of any appropriate conductive
material (e.g., gold, platinum, doped silicon, nickel, silver,
iridium, tungsten, titanium, titanium nitride, aluminum, cadmium,
chromium, molybdenum, lead, etc.) onto the filament substrate. In
still other variations, however, Block S220 can alternatively or
additionally comprise metalizing the filament substrate by plating
or evaporating a layer of any appropriate conductive material onto
the filament substrate, or by applying the conductive material
(e.g., nickel, gold, platinum, doped silicon, tungsten, iridium,
titanium nitride) in any other suitable manner. In addition to
applying the conductive material to the sharp tips of the array of
protrusions defined in Block S210, Block S220 can include coupling
a second conductive layer to a second surface of the substrate
(e.g., a surface of the substrate directly opposing the array of
protrusions), in order to define a second conductive surface of the
substrate to facilitate electrical coupling for signal transmission
(e.g., upon detection of an analyte).
[0052] Preferably, Block S220 comprises applying the conductive
layer to the filament substrate in a substantially uniform manner
(e.g., as an even layer with substantially uniform thickness);
however, Block S220 can alternatively comprise applying the
conductive layer to the filament substrate in a non-uniform manner,
such that some regions of the conductive layer are thicker than
others. Furthermore, Block S220 can include application of multiple
layers of one or more conductive materials, in order to form a
conductive layer comprising multiple layers of materials. In
variations involving sputtering or evaporation, the filament
substrate can be translated or rotated while being sputter coated
or evaporation coated to facilitate uniform deposition of the
conductive layer. In variations involving plating to apply the
conductive layer, the plating can be applied using chemical or
electrochemical plating, to any appropriate thickness.
[0053] Block S230 recites defining an active region and a
non-active region of the filament with an insulating layer, and
functions to form at least one insulating region of a filament of
the microsensor. Preferably, Block S230 comprises applying an
insulating layer to a portion of the filament substrate/conductive
layer assembly, in a manner wherein at least one region of the
conductive layer is not covered (e.g., uncovered, exposed,
unsheathed) with the insulating layer (thus forming the active and
non-active regions of the filament). Block S230 can be performed
using thermal oxide growth, spin coating, spray coating, or any
other appropriate method of depositing a localized layer of an
insulting material. Preferably, the insulating layer is composed of
an insulating oxide; however, the insulating layer can additionally
or alternatively include an insulating polymer (e.g., polyimide,
cyanate ester) that is chemical and heat resistant and/or any
appropriate material (e.g., thermally grown silicon oxide, chemical
vapor deposited oxides, titanium oxide, tantalum oxide, other
oxides, chemical vapor deposited nitrides, other nitrides,
paralene, etc.) that is configured to insulate a portion of the
filament substrate/conductive layer assembly. Furthermore, in Block
S230, the insulating layer can be grown or deposited uniformly or
non-uniformly over desired surfaces (e.g., all exposed surfaces,
active regions formed through bulk material removal, active regions
defined by chemical etching, plasma etching, high energy etching,
any other suitable type of etching, etc.).
[0054] In a first example of Block S230, an oxide layer can be
formed at exposed surfaces of the substrate (e.g., all exposed
surfaces of the substrate, of substrate cores of protrusions, cut
surfaces, etc.), by a thermal oxide growth process. The oxide layer
preferably couples to the exposed surfaces of the substrate in a
manner that discourages unbonding or removal of the oxide material
during subsequent Blocks of the method 200. In the first example,
the oxide layer is formed by way of a thermal oxide growth process
at 900-1050 C for 1-2 hours, in order to induce 0.1-10 .mu.m thick
thermal oxide growth. In variations of the first example, however,
the oxide layer can be formed at the substrate or coupled to the
substrate using a thermal process defined by any suitable
temperature parameters, for any suitable duration of time, in order
to define an oxide layer of any other suitable thickness.
[0055] In a second example of Block S230', as shown in FIG. 7A, an
insulating polymer (e.g., polyimide, cyanate ester) can be
deposited over the substrate or substrate/conductive layer
subassembly S231. The insulator may then be soft-baked S232 to
facilitate selective removal of the insulating polymer. In the
second example, the tip regions of the filaments can then be
exposed by selectively dissolving or etching the soft-baked
insulating polymer S233, and the tip regions of the filaments can
be cleaned S234 (e.g., using a plasma-etching process). Finally,
the filament assembly comprising active and non-active regions can
be hard-baked to cure the insulating polymer S235. In a variation
of the second example, the insulating polymer can be
photosensitive, such that Block S232 uses a photolithographic
process to selectively expose areas above filaments or between
filaments (to increase solubility), and so that the a positive
photolithographic process or a negative photolithographic process
can be used to define the active/non-active regions. Additionally,
Block S235 can use a photo-crosslinking process to cure the
insulating polymer.
[0056] In a third example of Block S230'', as shown in FIG. 7B, a
set of oxide caps coupled to filament tips (produced, for instance,
during a Bosch or DRIE process) can be used to shield the filament
tips S236, and a dielectric or other insulating material can be
applied to define active and non-active regions S237. The
insulating material in the third example can be applied using a
line of sight deposition method, preferably at an angle, such that
the insulating material is applied only to specific regions (e.g.,
between filament tips). The line of sight deposition method can be
an evaporation method (e.g., to deposit an insulating polymer), or
can additionally or alternatively be a sputtering method (e.g.,
sputtering of titanium or tantalum), followed by oxidation to
produce the insulating layer. The filament assembly can then be
passivated (e.g., during a DRIE process) and the oxide caps can be
removed (e.g., pinched off) to expose the active regions.
[0057] In a fourth example of Block S230''', as shown in FIG. 7C,
the insulating material can be fluidly deposited between filament
structures (e.g., by inkjet printing, silk screening, dispensing)
S238. The insulating material can be a molten polymer (e.g.,
nylon), or can be a polymer that is in solution form (e.g.,
silicon, polyurethane, polyimide) that is subsequently cured S235'
(e.g., baking, photo-crosslinking) to remove solvent and form the
active and non-active regions.
[0058] In a fifth example of Block S230'''', as shown in FIG. 7D, a
photoresist can be applied to the substrate or substrate/conductive
layer subassembly S239, and then etched away to expose filament
tips S271. The tips may then be protected with a intermediary layer
(e.g., metal or soluble insulator) S272, the photoresist can be
removed by further etching S273, and then non-tip regions may then
be passivated to form non-active insulating regions S274. Finally,
the intermediary layer can be removed to define the active regions
S275. Block S230 can alternatively comprise any other suitable
method of defining an active region and a non-active region of the
filament with an insulating layer.
[0059] In a sixth example of Block S230''''', the insulating
material (e.g., parylene) used to define the active regions and
non-active regions can also be deposited by a chemical vapor
deposition (CVD) process. In this example, the tips of the
filaments can be protected with a temporary protective layer (e.g.,
by covering each needle tip photolithographically using photoresist
or applying a small droplet of photoresist or other soluble polymer
to each filament tip). Then, the insulating material (e.g.,
parylene) can be deposited in a CVD process to conformally coat the
unprotected filament areas. After deposition of the insulating
material, the temporary protective layer can be removed (e.g., by
using an appropriate solvent), to form the active and the
non-active regions.
[0060] In variations of the method 200, Blocks S220 and S230 can be
performed in any suitable order, in relation to defining an array
of sharp tips in variations of Block S210, and in order to define
active/non-active regions. In a first variation of the method 200,
forming an array of columnar protrusions S211b at the substrate can
be performed prior to forming an insulating layer at exposed
surfaces of the substrate in Block S230. Then, the insulating layer
can be selectively removed, as desired, from surfaces of the
substrate (e.g., at a surface of the substrate directly opposing
that of the array of columnar protrusions). After selective removal
of the insulating layer, an array of sharp protrusions can be
formed at distal ends of the array of columnar protrusions in
variations of the method including Block S211a, and the conductive
layer can be coupled to all regions of the substrate not covered by
the insulating layer, thereby coupling the conductive layer to at
least the tip regions of the array of protrusions in a variation of
Block S220. As such, active region/non-active regions can be
defined through bulk material removal (e.g., cutting, dicing) or
any other suitable process including one or more of: selective
chemical etching, plasma etching, high energy etching, and any
other suitable etching method.
[0061] In a second variation, which can extend from the first
variation, the method 200 can include Blocks S210, S220, and S230,
and further include using a sacrificial layer to selectively
isolate a region of the substrate during processing S283, in order
to facilitate processing of the conductive layer and/or the
insulating layer in Blocks S220 and S230, respectively. The
sacrificial layer can include a nitride material (e.g., 1000-2500
.ANG. thick nitride), an oxide material, a carbide material, a
salt, a sugar, a polymer (e.g., polyethylene glycol), and/or any
other suitable material that does not deteriorate during subsequent
processing steps. Furthermore, the sacrificial layer can be
bioabsorbable and/or porous to facilitate biocompatibility and/or
processing. In one example, forming an array of sharp protrusions
S211a can be performed prior to coupling a conductive layer to the
array of sharp protrusions and any other desired surface of the
substrate (e.g., a surface directly opposing that of the array of
sharp protrusions), as in variations of Block S230, followed by
coupling of a sacrificial layer to all surfaces of the substrate
with the conductive layer. In this example, an array of columnar
protrusions can be formed as in Block S211b by removing material
between the array of sharp protrusions, after which an insulating
layer can be generated at all exposed surfaces of the substrate, as
in Block S230. The sacrificial layer can then be removed prior to
subsequent processing steps. In another example, forming an array
of sharp protrusions S211a can be performed prior to coupling of a
sacrificial layer, as in Block S283, at all surfaces of the
substrate intended to be coupled to a conductive layer. Material
can then be removed between the array of sharp protrusions to form
an array of columnar protrusions, as in Block S211b, after which an
insulating layer can be formed at all exposed surfaces of the
substrate, as in Block S230. Then, the sacrificial layer can be
removed and the conductive layer can be coupled to all regions of
the substrate formerly occupied by the sacrificial layer, as in
variations of Block S220. In other examples, coupling of the
sacrificial layer can be omitted or performed at any suitable stage
of the method 200, specific examples of which are described in
further detail below.
[0062] As shown in FIG. 8A, in a first specific example of
processing the substrate, the conductive layer, and the sensing
layer in Blocks S210, S220, and S230, material is removed from a
first surface of the substrate, thereby forming an array of
columnar protrusions as in Block S211b. Removing material in the
first specific example is performed by way of a non-angled blade of
a dicing saw in order to remove material from the first surface of
the substrate to a desired depth of .about.400 .mu.m, a width of
100 .mu.m, and a gap of 500 .mu.m, at a cutting rate of 2-3 mm/s.
In the first specific example, the dicing saw is configured to form
the array of columnar protrusions through adjacent cuts in a first
direction, followed by adjacent cuts in a second direction
orthogonal to the first direction, thereby forming a 2-dimensional
array of columnar protrusions. In the first specific example, the
substrate is composed of P-type, boron-doped, <100>
orientation silicon with a resistivity of 0.005-0.01 ohm-cm, a
thickness from 500-1500 .mu.m, a total thickness variation (TTV) of
<10 .mu.m, and with a first surface side polish. Subsequent to
formation of the array of columnar protrusions, an insulating layer
of .about.1 .mu.m oxide is formed at all exposed surfaces of the
substrate, as in Block S240, by inducing thermal oxide growth at
900-1050 C for 1-2 hours. Then, the insulating layer is removed
from a second surface of the substrate, directly opposing the
surface of the substrate at which the columnar protrusions were
formed, by way of a directed plasma etch. Subsequently, an array of
sharp protrusions is formed, as in Block S211a, by removing
material from the distal end of each columnar protrusion. Forming
an array of sharp protrusions is performed by way of a 500 .mu.m,
60-degree angled blade of a dicing saw configured to cut 2-facet
tips at a rate of 4 mm/s. Similar to forming the array of columnar
protrusions, the dicing saw is configured to form the array of
sharp protrusions through adjacent cuts in a first direction,
followed by adjacent cuts in a second direction orthogonal to the
first direction, thereby forming a 2-dimensional array of sharp
protrusions (i.e., sharp tips). Lastly, in the first specific
example, a conductive layer is coupled to the array of sharp
protrusions and the second surface of the substrate by
electroplating (e.g., of nickel, of gold, and/or of platinum), as
in Block S220.
[0063] As shown in FIG. 8B, in a second specific example of
processing the substrate, the conductive layer, and the sensing
layer in Blocks S210, S220, and S230, material is removed from a
first surface of the substrate, thereby forming an array of
columnar protrusions as in Block S211b. Removing material in the
second specific example is performed by way of a non-angled blade
of a dicing saw in order to remove material from the first surface
of the substrate to a desired depth of .about.400 .mu.m, a width of
100 .mu.m, and a gap of 500 .mu.m, at a cutting rate of 2-3 mm/s.
In the second specific example, the dicing saw is configured to
form the array of columnar protrusions through adjacent cuts in a
first direction, followed by adjacent cuts in a second direction
orthogonal to the first direction, thereby forming a 2-dimensional
array of columnar protrusions. In the second specific example, the
substrate is composed of P-type, boron-doped, <100>
orientation silicon with a resistivity of 0.005-0.01 ohm-cm, a
thickness from 500-1500 .mu.m, a total thickness variation (TTV) of
<10 .mu.m, and with a first surface side polish. Subsequent to
formation of the array of columnar protrusions, an insulating layer
of .about.1 .mu.m oxide is formed at all exposed surfaces of the
substrate, as in Block S230, by inducing thermal oxide growth at
900-1050 C for 1-2 hours. Then, the insulating layer is removed
from a second surface of the substrate, directly opposing the
surface of the substrate at which the columnar protrusions were
formed, by way of a directed plasma etch. Following removal of the
insulating layer from the second surface, a sacrificial layer is
coupled to all surfaces of the substrate still coupled to the
insulating layer. Subsequently, an array of sharp protrusions is
formed, as in Block S211a, by removing material from the distal end
of each columnar protrusion. Forming an array of sharp protrusions
is performed by way of a 500 .mu.m, 60-degree angled blade of a
dicing saw configured to cut 2-facet tips at a rate of 4 mm/s.
Similar to forming the array of columnar protrusions, the dicing
saw is configured to form the array of sharp protrusions through
adjacent cuts in a first direction, followed by adjacent cuts in a
second direction orthogonal to the first direction, thereby forming
a 2-dimensional array of sharp protrusions (i.e., sharp tips).
Lastly, in the second specific example, a conductive layer is
coupled to the array of sharp protrusions and the second surface of
the substrate by electroplating (e.g., of nickel, of gold, and/or
of platinum) as in Block S220, followed by removal of the
sacrificial layer from the insulating layer. The sacrificial layer,
in the second specific example, thus functions to facilitate
isolation of the conductive layer to desired surfaces, such that
the conductive layer does not substantially overlap with the
insulating layer in an undesired manner.
[0064] As shown in FIG. 8C, in a third specific example of
processing the substrate, the conductive layer, and the sensing
layer in Blocks S210, S220, and S230, material is removed from a
first surface of the substrate to form an array of sharp
protrusions (e.g., sharp tips), as in Block S211a. Forming an array
of sharp protrusions is performed by way of a 500 .mu.m, 60-degree
angled blade of a dicing saw configured to cut 2-facet tips at a
rate of 4 mm/s. In the third specific example, the dicing saw is
configured to form the array of sharp protrusions through adjacent
cuts in a first direction, followed by adjacent cuts in a second
direction orthogonal to the first direction, thereby forming a
2-dimensional array of sharp protrusions. In the third specific
example, the substrate is composed of P-type, boron-doped,
<100> orientation silicon with a resistivity of 0.005-0.01
ohm-cm, a thickness from 500-1500 .mu.m, a total thickness
variation (TTV) of <10 .mu.m, and with a first surface side
polish. Subsequent to forming the array of sharp protrusions, a
conductive layer is coupled to the array of sharp protrusions and a
second surface of the substrate, directly opposed to the array of
sharp protrusions, as in Block S220, by depositing 1000 .ANG. of
platinum, 1000 .ANG. of iridium, 1000 .ANG. of tungsten, and 100
.ANG. of titanium nitride at the desired surfaces. In variations of
the third specific example, the conductive layer can include: a
1000 .ANG. thick platinum layer and a 100 .ANG. thick titanium
layer, a 1000 .ANG. thick platinum layer and a 100 .ANG. thick
titanium nitride layer, a 1000 .ANG. thick iridium layer and a 100
.ANG. thick titanium nitride layer, or a 1000 .ANG. thick tungsten
layer. A sacrificial layer comprising a 1000-2500 .ANG. thick layer
of nitride is then coupled to the conductive layer, as in Block
S283, and material is removed from the substrate between each sharp
protrusion in the array of sharp protrusions, thereby forming an
array of columnar protrusions coupled to the array of sharp
protrusions, as in Block S211b. Forming the array of columnar
protrusions is performed by way of a non-angled blade of a dicing
saw in order to remove material from the first surface of the
substrate to a desired depth of .about.400 .mu.m, a width of 100
.mu.m, and a gap of 500 .mu.m, at a cutting rate of 2-3 mm/s. In
the third specific example, the dicing saw is configured to form
the array of columnar protrusions through adjacent cuts in a first
direction, followed by adjacent cuts in a second direction
orthogonal to the first direction, thereby forming a 2-dimensional
array of columnar protrusions. An insulating layer is formed at all
exposed surfaces (e.g., cut surfaces without conductive layer or
sacrificial layer) of the substrate, as in Block S230, by inducing
thermal oxide growth to a thickness of 1 .mu.m at 900-1050 C for
1-2 hours. Then, the sacrificial layer is removed by a directed
plasma etch.
[0065] As shown in FIG. 8D, in a fourth specific example of
processing the substrate, the conductive layer, and the sensing
layer in Blocks S210, S220, and S230, material is removed from a
first surface of the substrate to form an array of sharp
protrusions (e.g., sharp tips), as in Block S211a. Forming an array
of sharp protrusions is performed by way of a 500 .mu.m, 60-degree
angled blade of a dicing saw configured to cut 2-facet tips at a
rate of 4 mm/s. In the fourth specific example, the dicing saw is
configured to form the array of sharp protrusions through adjacent
cuts in a first direction, followed by adjacent cuts in a second
direction orthogonal to the first direction, thereby forming a
2-dimensional array of sharp protrusions. In the fourth specific
example, the substrate is composed of P-type, boron-doped,
<100> orientation silicon with a resistivity of 0.005-0.01
ohm-cm, a thickness from 500-1500 .mu.m, a total thickness
variation (TTV) of <10 .mu.m, and with a first surface side
polish. A sacrificial layer comprising a 1000-2500 .ANG. thick
layer of nitride is then coupled to the array of sharp protrusions
and to a second surface of the substrate directly opposing the
array of sharp protrusions, as in Block S283, and material is
removed from the substrate between each sharp protrusion in the
array of sharp protrusions, thereby forming an array of columnar
protrusions coupled to the array of sharp protrusions, as in Block
S211b. Forming the array of columnar protrusions is performed by
way of a non-angled blade of a dicing saw in order to remove
material from the first surface of the substrate to a desired depth
of .about.400 .mu.m, a width of 100 .mu.m, and a gap of 500 .mu.m,
at a cutting rate of 2-3 mm/s. In the fourth specific example, the
dicing saw is configured to form the array of columnar protrusions
through adjacent cuts in a first direction, followed by adjacent
cuts in a second direction orthogonal to the first direction,
thereby forming a 2-dimensional array of columnar protrusions. An
insulating layer is formed at all exposed surfaces (e.g., cut
surfaces without sacrificial layer) of the substrate, as in Block
S230, by inducing thermal oxide growth to a thickness of 1 .mu.m at
900-1050 C for 1-2 hours. Then, the sacrificial layer is removed by
a directed plasma etch. Subsequent to removal of the sacrificial
layer, a conductive layer is coupled to the array of sharp
protrusions and a second surface of the substrate, directly opposed
to the array of sharp protrusions, as in Block S220, by depositing
1000 .ANG. of platinum, 1000 .ANG. of iridium, 1000 .ANG. of
tungsten, and 100 .ANG. of titanium nitride at the desired
surfaces. In variations of the fourth specific example, the
conductive layer can include: a 1000 .ANG. thick platinum layer and
a 100 .ANG. thick titanium layer, a 1000 .ANG. thick platinum layer
and a 100 .ANG. thick titanium nitride layer, a 1000 .ANG. thick
iridium layer and a 100 .ANG. thick titanium nitride layer, or a
1000 .ANG. thick tungsten layer. Other variations of the fourth
specific example can include electroplating of any suitable metal
(e.g., nickel, gold, platinum).
[0066] As shown in FIG. 8E, in a fifth specific example of
processing the substrate, the conductive layer, and the sensing
layer in Blocks S210, S220, and S230, an array of sharp
protrusions, with a tapered profile (i.e., tapering from a tip end
toward a base end coupled to the substrate), is formed at a first
surface of a substrate by a DRIE process, as in Block S210. A
conductive layer is then coupled to all exposed surfaces of the
substrate, as in Block S220 by depositing 1000 .ANG. of platinum,
1000 .ANG. of iridium, 1000 .ANG. of tungsten, and 100 .ANG. of
titanium nitride at the exposed surfaces. In variations of the
fifth specific example, the conductive layer can include: a 1000
.ANG. thick platinum layer and a 100 .ANG. thick titanium layer, a
1000 .ANG. thick platinum layer and a 100 .ANG. thick titanium
nitride layer, a 1000 .ANG. thick iridium layer and a 100 .ANG.
thick titanium nitride layer, or a 1000 .ANG. thick tungsten layer.
Other variations of the fifth specific example can include
electroplating of any suitable metal (e.g., nickel, gold, platinum)
to form the conductive layer. Subsequent to formation of the
conductive layer, an insulating layer comprising a nitride material
is then coupled to the conductive layer, as in Block S230, and a
sacrificial layer is then coupled to the insulating layer, as in
Block S283, at regions of the substrate between the base ends of
the array of sharp protrusions. In the fifth specific example, the
sacrificial layer is applied by way of a spin photoresist.
Subsequently, the insulating layer is removed from the tip regions
of the array of sharp protrusions and from a second surface of the
substrate, directly opposed to the array of sharp protrusions, by
way of an anisotropically directed plasma field. Lastly, the
sacrificial layer is removed (e.g., by etching).
[0067] In other examples of the method 200, processing the
substrate, the conductive layer, and the sensing layer in Blocks
S210, S220, and S230 can be performed according to any other
suitable process and in any other suitable order. Furthermore, in
variations of the described processes, any suitable number of
blades, cutting surfaces, other tool for removal of material can be
used to increase processing speed/efficiency.
2.2 Manufacturing Method--Sensing Layer and Selective Layer
Processing
[0068] Block S240 recites applying a sensing layer to at least the
conductive layer, and functions to form a filament coating that
enables transduction of an ionic concentration to an electronic
voltage. Preferably, the sensing layer is applied selectively to
the filament substrate/conductive layer/insulating layer assembly
at regions where the conductive layer is exposed (e.g., only at
active regions); however, the sensing layer can alternatively be
applied to the entire filament substrate/conductive
layer/insulating layer assembly. In variations wherein the sensing
layer is applied selectively to the filament substrate/conductive
layer/insulating layer assembly, Block S240 can comprise
electrodeposition, lithography, inkjet printing, screen printing,
or any other appropriate method for applying the sensing layer
selectively. In variations wherein the sensing layer is applied to
the entire filament substrate/conductive layer/insulating layer
assembly, Block S240 can comprise glazing, spin coating, spray
coating, or any method of applying a polymer coating in a
non-selective manner. Preferably, the sensing layer is composed of
a material with reversible redox reaction behavior, as previously
described. In one example, the sensing layer can comprise a
nitrogen-containing polymer, such as polypyrrole or polyaniline.
The sensing layer can additionally or alternatively be composed of
any appropriate conductive material. In another example, the
sensing layer can additionally or alternatively comprise a protein
or peptide serving as a complementary molecule to an analyte, such
as glucose oxidase for glucose sensing or valinomycin for potassium
sensing. In variations of this example, the sensing layer can
comprise amino acids (e.g., lysine) and/or polymer chains of
subsequently associated amino acids (e.g., poly-lysine). In
providing a protein distribution, an amino acid distribution, a
polymer chain distribution, and/or any other particle distribution
at the sensing layer in Block S240, the distribution can be uniform
or non-uniform (e.g., concentrated in desired regions, concentrated
at a surface, etc.), homogenous or heterogeneous, and generated in
any suitable manner.
[0069] In some variations, Block S240 can include forming a notch
at least at one sharp protrusion (i.e., sharp tip) of the array of
sharp protrusions S242 formed, as in Block S211a. The notch, as
shown in FIG. 9, can be used as a pocket to isolate the sensing
layer, and can additionally or alternatively be filled with any
other suitable functional material. In one such variation, the
notch can be filled with a protective material that functions to
protect the sensing layer during insertion or during a period of
contact with the user's body fluid. In another variation, the notch
can be filled with a "calibration material" configured to provide
or release an analyte according to a known profile (e.g., release
profile, concentration, degradation profile, etc.). In another
variation, the notch can be filled with a therapeutic substance to
facilitate delivery of the therapeutic substance to a user in a
drug delivery application. The notch can be formed in alignment
with a sharp tip of a filament, or can alternatively be form in
misalignment with a warp tip of a filament. Variations of Block
S240 can entirely omit forming the notch, or can including
providing a notch for any other suitable purpose.
[0070] Some variations of the method can further include Block
S245, which recites: coupling an intermediate selective layer to
the conductive layer defined in Block S220. In a variation wherein
another layer (e.g., an intermediate active layer that facilitates
transduction, as described in Section 1 above) is coupled
superficial to the conductive layer defined in Block S220, the
method can include a variation of Block S245 as Block S246, which
recites: providing an intermediate selective layer able to transmit
a signal to the conductive layer, and coupling the sensing layer
defined in Block S240 to the intermediate selective layer. Blocks
S245 and S246 function to provide an additional selective layer to
facilitate detection of an analyte (e.g., glucose) in a selective
manner. In some variations, Blocks S245 and S246 can include
applying a polymer superficial to the conductive layer, and
polymerizing the polymer to set the intermediate selective layer.
In specific examples of Blocks S245 and S246, the intermediate
selective layer can include phenylenediamine for glucose sensing,
which is electropolymerized to set the intermediate selective
layer. Other variations of these specific examples can include
polymerization of any other suitable material in any other suitable
manner (e.g., chemical polymerization, heat polymerization,
photopolymerization, etc.). Other variations of Blocks S245 and
S246 can alternatively include providing a non-polymeric material
as the intermediate sensing layer, which can be processed in any
other suitable manner.
[0071] Block S250 recites forming a selective layer, and functions
to form a layer configured to facilitate sensing of specific target
analytes. Preferably, Block S250 comprises forming a selective
layer comprising a polymer matrix with a distribution of
complementary molecules S252 to at least one target analyte
characterizing a user's body chemistry. Block S252 preferably
comprises forming a homogenous mixture of the polymer matrix
material (e.g., in either a solution or gel phase) with the
distribution of complementary molecules, but can alternatively
comprise forming a heterogeneous mixture of the polymer matrix
material with the distribution of complementary molecules.
Alternatively, Block S252 can be replaced by Block S254, which
comprises depositing a layer of a polymer matrix and depositing the
distribution of complementary molecules, onto the assembly produced
after Block S240, in any order. In still another alternative, Block
S250, S252 and/or Block S254 can be performed prior to one or more
of Blocks S220, S230, and S240, such that a selective layer is
deposited at different times and/or different locations during
processing of the microsensor. In one such example, in a sensor for
glucose detection applications, Block S250 is performed subsequent
to Block S220 (e.g., immediately over the conductive layer). In
another example, with a conductive substrate, Block S250 can be
performed subsequent to Block S210 (e.g., a selective layer can be
deposited onto a tip region of the conductive substrate). Forming a
selective layer comprising a polymer matrix can further comprise
forming a selective layer with a polymer matrix and a plasticizer,
in embodiments wherein a flexible polymer matrix is desired for
Block S250. In one specific example, the polymer matrix comprises
polyvinyl chloride (PVC) with a plasticizer to increase
flexibility; however, in other variations, the polymer matrix can
be composed of any appropriate polymer (e.g., polyethylene,
polytetrafluoroethylene, urethane, polyurethane, phenylenediamine,
ortho-phenylenediamine, protein matrices, amino acid matrices,
etc.), with or without a plasticizer, and configured to contain a
distribution of complementary molecules. Again, in one example, the
distribution of complementary molecules comprises glucose oxidase
molecules for glucose sensing, and in another example, the
distribution of complementary molecules comprises valinomycin
molecules for potassium sensing. Block S250 can be performed by
spin coating a polymer matrix-complementary molecule mixture with
or without a plasticizer, by drop casting a polymer
matrix-complementary molecule mixture with or without a
plasticizer, or by any appropriate method. Additionally, spin
coating, drop casting, electrodeposition, electroplating, or any
other suitable method of application can be performed in stages,
such that the selective layer is characterized by a tunable
thickness. The tunable thickness preferably governs a rate at which
complementary molecules bind to target analytes (e.g., diffusion
rate), and governs the amount (e.g., concentration or total amount)
of complementary molecules within the selective layer and/or
defines a molecular size cut-off.
[0072] In some variations, in particular, variations of
manufacturing a microsensor for glucose sensing, the method 200 can
additionally or alternatively include Block S256, which recites:
providing a stabilizing layer configured to stabilize the sensing
layer. Block S256 preferably functions to stabilize a glucose
oxidase sensing layer, in manufacturing a microsensor for glucose
sensing; however, Block S256 can additionally or alternatively
function to stabilize the sensing layer for any other suitable
application. In some variations, Block S256 can include providing a
polymer superficial to the sensing layer, and polymerizing the
polymer to set the intermediate selective layer. In specific
examples of Block S256, the stabilizing layer can include
phenylenediamine for glucose sensing, which is electropolymerized
to set the stabilizing layer. Other variations of this specific
example can include polymerization of any other suitable material
in any other suitable manner (e.g., chemical polymerization, heat
polymerization, photopolymerization, etc.). Other variations of
Block S256 can alternatively include providing a non-polymeric
material as the intermediate sensing layer, which can be processed
in any other suitable manner.
[0073] In some variations, in particular, variations of
manufacturing a microsensor for glucose sensing, the method 200 can
additionally or alternatively include Block S258, which recites:
providing an intermediate protective layer superficial to the
sensing layer. Block S258 preferably functions to form a layer that
provides intermediate protection and/or block transport of
undesired species. In some variations, Block S258 can include
providing a polymer superficial to the sensing layer, including at
least one functional compound configured to provide a protective
barrier. In examples, the polymer of the intermediate protective
layer can include any one or more of: teflon, chlorinated polymer,
nafion, polyethylene glycol, and any other suitable polymer, and
can include functional compounds including one or more of: lipids,
charged chemical species that block transport of charged species,
surfactants, and any other suitable compound. Other variations of
Block S258 can alternatively include providing a non-polymeric
material as the intermediate protective layer, which can be
processed in any other suitable manner.
[0074] The method 200 can additionally or alternatively include any
other suitable Blocks or Steps configured to generate an array of
filaments for analyte sensing during contact with a body fluid of
the user. As such, the method 200 can include any one or more of:
coupling an adhesion layer to any suitable layer used during the
method, wherein the adhesion layer functions to facilitate
maintenance of coupling of the layer(s) for robustness; coupling a
temporary functional layer to the selective layer, which
facilitates penetration into the body of the user and/or
calibration of the microsensor; providing a functional external
layer configured to suppress or prevent an inflammatory response
(e.g., by comprising a surface treatment or an anti-inflammatory
agent), prevent bio-rejection, prevent encapsulation (e.g., by
comprising a bio-inert substance, such as pyrolytic carbon),
enhance target analyte/ion detection, and/or provide any other
suitable anti-failure mechanism; and processing the substrate
according to any other suitable process.
[0075] The FIGURES illustrate the architecture, functionality and
operation of possible implementations of systems, methods and
computer program products according to preferred embodiments,
example configurations, and variations thereof. In this regard,
each block in the flowchart or block diagrams may represent a
module, segment, step, or portion of code, which comprises one or
more executable instructions for implementing the specified logical
function(s). It should also be noted that, in some alternative
implementations, the functions noted in the block can occur out of
the order noted in the FIGURES. For example, two blocks shown in
succession may, in fact, be executed substantially concurrently, or
the blocks may sometimes be executed in the reverse order,
depending upon the functionality involved. It will also be noted
that each block of the block diagrams and/or flowchart
illustration, and combinations of blocks in the block diagrams
and/or flowchart illustration, can be implemented by special
purpose hardware-based systems that perform the specified functions
or acts, or combinations of special purpose hardware and computer
instructions.
[0076] As a person skilled in the art will recognize from the
previous detailed description and from the figures and claims,
modifications and changes can be made to the preferred embodiments
of the invention without departing from the scope of this invention
defined in the following claims.
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