U.S. patent application number 16/848698 was filed with the patent office on 2021-10-14 for fiber optic integrated-light diffusers for sensing applications.
The applicant listed for this patent is Khalifa University of Science and Technology, The University of Birmingham. Invention is credited to Haider BUTT, Mohamed ELSHERIF.
Application Number | 20210318489 16/848698 |
Document ID | / |
Family ID | 1000005866186 |
Filed Date | 2021-10-14 |
United States Patent
Application |
20210318489 |
Kind Code |
A1 |
BUTT; Haider ; et
al. |
October 14, 2021 |
FIBER OPTIC INTEGRATED-LIGHT DIFFUSERS FOR SENSING APPLICATIONS
Abstract
Embodiments include a fiber optic probe comprising an optical
fiber, and a sensor component attached to the optical fiber, the
sensor component including an asymmetric microlens array imprinted
on a stimuli-responsive hydrogel. Embodiments further include a
method of fabricating a fiber optic probe comprising depositing a
stimuli-responsive hydrogel precursor solution on a substrate mold,
the substrate mold including a concave asymmetric microlens array;
contacting an end of an optical fiber with the stimuli-responsive
hydrogel precursor solution deposited on the substrate mold; and
exposing the end of the optical fiber and the stimuli-responsive
hydrogel precursor solution to light to form a stimuli-responsive
hydrogel sensor imprinted with a convex asymmetric microlens array
and attached to the end of the optical fiber. Embodiments further
include systems comprising the fiber optic probes.
Inventors: |
BUTT; Haider; (Abu Dhabi,
AE) ; ELSHERIF; Mohamed; (Birmingham, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Khalifa University of Science and Technology
The University of Birmingham |
Abu Dhabi
Birmingham |
|
AE
GB |
|
|
Family ID: |
1000005866186 |
Appl. No.: |
16/848698 |
Filed: |
April 14, 2020 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G02B 6/32 20130101; B29D
11/00442 20130101; G02B 3/0056 20130101; G02B 6/0025 20130101; G02B
6/02338 20130101; G02B 2006/12138 20130101 |
International
Class: |
G02B 6/02 20060101
G02B006/02; F21V 8/00 20060101 F21V008/00; G02B 6/32 20060101
G02B006/32; G02B 3/00 20060101 G02B003/00; B29D 11/00 20060101
B29D011/00 |
Claims
1. A fiber optic probe comprising: an optical fiber, and a sensor
component attached to the optical fiber, the sensor component
including light diffusing microstructures imprinted on a
stimuli-responsive hydrogel, wherein the light diffusing
microstructures form an asymmetric microlens array.
2. The fiber optic probe of claim 1, wherein the optical fiber is a
biocompatible hydrogel fiber.
3. The fiber optic probe of claim 1, wherein the asymmetric
microlens array includes one or more microlenses, each of the one
or more microlenses independently having a convex aspherical
surface, a plano-convex aspherical surface, a convex-concave
aspherical surface, a convex spherical surface, a plano-convex
spherical surface, or a convex-concave spherical surface.
4. The fiber optic probe of claim 1, wherein the asymmetric
microlens array has at least one of the following characteristics:
microlenses which are non-uniformly spaced apart; microlenses which
are arranged in a non-periodic configuration; microlenses which are
arranged in a non-ordered configuration; at least two microlenses
having different surface topologies; at least two microlenses
having different base geometries; and at least two microlenses
having different heights.
5. A fiber optic probe of claim 1, wherein the sensor component
includes a glucose-responsive hydrogel.
6. The fiber optic probe of claim 5, wherein the glucose-responsive
hydrogel sensor includes acrylamide; N,N'-methylenebisacrylamide;
3-(acrylamido)-phenylboronic acid (3-APBA); and
2,2-dimethoxy-2-2phenylacetophenone (DMPA).
7. A fiber optic probe of claim 1, wherein the sensor component
includes an alcohol-responsive hydrogel.
8. The fiber optic probe of claim 7, wherein the alcohol-responsive
hydrogel sensor includes 2-hydroxyethylmethacrylate (HEMA);
ethylene glycol dimethacrylate (EGDMA); and
2,2-dimethoxy-2-phenylacetophenone (DMPA).
9. A fiber optic probe of claim 1, wherein the sensor component
includes a pH-responsive hydrogel.
10. The fiber optic probe of claim 9, wherein the pH-responsive
hydrogel sensor includes 2-hydroxyethylmethacrylate (HEMA);
ethylene glycol dimethacrylate (EGDMA); acrylic acid (AA); and
2,2-dimethoxy-2-phenylacetophenone (DMPA).
11. A method of fabricating a fiber optic probe, comprising: (a)
depositing a light-curable stimuli-responsive hydrogel precursor
solution on a substrate mold having a surface including an inverse
asymmetric microlens array; (b) contacting an end portion of an
optical fiber with the light-curable stimuli-responsive hydrogel
precursor solution deposited on the substrate mold; and (c)
exposing the end portion of the optical fiber and light-curable
stimuli-responsive hydrogel precursor solution to light to form a
stimuli-responsive hydrogel sensor imprinted with an asymmetric
microlens array and attached to the end portion of the optical
fiber.
12. The method of claim 11, wherein the light-curable
stimuli-responsive hydrogel is synthesized, imprinted with the
asymmetric microlens array, and attached to the end portion of the
optical fiber in step (c).
13. The method of claim 11, wherein the light-curable
stimuli-responsive hydrogel precursor solution includes at least
the following: a monomer, a crosslinking agent, and a
photoinitiator.
14. The method of claim 11, wherein the substrate mold is
fabricated by: depositing a light-curable prepolymer solution on a
master light diffuser having a surface including a master
asymmetric microlens array; exposing the deposited light-curable
prepolymer solution to light to cure the prepolymer; and releasing
the cured prepolymer from the master light diffuser to obtain the
substrate mold, the substrate mold including the inverse asymmetric
microlens array.
15. The method of claim 11, wherein the optical fiber is fabricated
by: injecting a light-curable monomer solution into a tubular body;
exposing the monomer solution to light to initiate polymerization;
and extracting a polymerized fiber from the tubular body to obtain
the optical fiber.
16. The method of claim 11, wherein the asymmetric microlens array
includes one or more microlenses, each of the one or more
microlenses independently having a convex aspherical surface, a
plano-convex aspherical surface, a convex-concave aspherical
surface, a convex spherical surface, a plano-convex spherical
surface, or a convex-concave spherical surface.
17. A system comprising: a fiber optic probe including an optical
fiber and a sensor component attached to the optical fiber, the
sensor component including an asymmetric microlens array imprinted
on a stimuli-responsive hydrogel; a light source coupled to the
fiber optic probe, wherein the light source is configured to
transmit light through the optical sensor; and a light sensor for
detecting light transmitted through the asymmetric microlens array
or light reflected from the asymmetric microlens array.
18. The system of claim 17, wherein the light sensor is a
smartphone used to detect light transmitted through the asymmetric
microlens array.
19. The system of claim 17, wherein the light sensor is an optical
power meter used to detect light reflected from the asymmetric
microlens array.
20. The system of claim 17, wherein the asymmetric microlens array
has at least one of the following characteristics: microlenses
having at least one of the following surfaces: a convex aspherical
surface, a plano-convex aspherical surface, a convex-concave
aspherical surface, a convex spherical surface, a plano-convex
spherical surface, and a convex-concave spherical surface;
microlenses which are non-uniformly spaced apart; microlenses which
are arranged in a non-periodic configuration; microlenses which are
arranged in a non-ordered configuration; at least two microlenses
having different surface topologies; at least two microlenses
having different base geometries; and at least two microlenses
having different heights.
Description
BACKGROUND
[0001] It has been reported that certain fiber optic probes can be
used for sensing applications. For example, fiber optic probes
based on Fabry-Perot interferometry, surface plasmon resonance,
amplitude absorbance measurements, and organic dyes have been
reported for sensing applications. However, these fiber optic
probes are limited in that they require high-quality films,
coherent light sources, high-cost instrumentation, bulky equipment,
complicated output signal processing, and complex fabrication
processes, among other things.
SUMMARY
[0002] According to one or more aspects, a fiber optic probe can
include an optical fiber, and a sensor component attached to the
optical fiber, the sensor component including an asymmetric
microlens array imprinted on a stimuli-responsive hydrogel.
[0003] According to one or more further aspects, a method of
fabricating a fiber optic probe can include (a) depositing a
light-curable stimuli-responsive hydrogel precursor solution on a
substrate mold having a surface including an inverse asymmetric
microlens array; (b) contacting an end portion of an optical fiber
with the light-curable stimuli-responsive hydrogel precursor
solution deposited on the substrate mold; and (c) exposing the end
portion of the optical fiber and light-curable stimuli-responsive
hydrogel precursor solution to light to form a stimuli-responsive
hydrogel sensor imprinted with an asymmetric microlens array and
attached to the end portion of the optical fiber.
[0004] According to one or more additional aspects, a system can
include a fiber optic probe including an optical fiber and a sensor
component attached to the optical fiber, the sensor component
including an asymmetric microlens array imprinted on a
stimuli-responsive hydrogel; a light source coupled to the fiber
optic probe, wherein the light source is configured to transmit
light through the optical sensor; and a light sensor for detecting
light transmitted through the asymmetric microlens array or light
reflected from the asymmetric microlens array.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1A is a schematic diagram of a fiber optic probe in
accordance with one or more embodiments of the invention.
[0006] FIG. 1B is a schematic diagram of an asymmetric microlens
array imprinted on a stimuli-responsive hydrogel in accordance with
one or more embodiments of the invention.
[0007] FIG. 1C is a schematic diagram showing the side profile of a
microlens array taken along line 1-1 in accordance with one or more
embodiments of the invention.
[0008] FIGS. 2A-2J are schematic diagrams showing the side profile
of various microlenses in accordance with one or more embodiments
of the invention.
[0009] FIG. 3 is a flowchart of a method of fabricating a fiber
optic probe in accordance with one or more embodiments of the
invention.
[0010] FIG. 4 is a flowchart of a method of fabricating a substrate
mold from a master light diffuser in accordance with one or more
embodiments of the invention.
[0011] FIG. 5 is a flowchart of a method of fabricating an optical
fiber in accordance with one or more embodiments of the
invention.
[0012] FIG. 6 is a schematic diagram of a system configured to
operate in transmission mode in accordance with one or more
embodiments of the invention.
[0013] FIG. 7 is a schematic diagram of a system configured to
operate in reflection mode in accordance with one or more
embodiments of the invention.
[0014] FIGS. 8A-8C are schematic diagrams illustrating (A) the
fabrication of a hydrogel sensor imprinted with an asymmetric
microlens array and constrained on a glass substrate, wherein a
monomer solution was pipetted onto a master of the asymmetric
microlens array and covered with a silanized glass slide before
being exposed to UV-light for curing; (B) the fabrication of a
biocompatible optical fiber, wherein a monomer solution was
injected into a tube mold and polymerized by UV-light, which was
then extracted by applying water pressure; (C) the fabrication of a
fiber optic probe in which an end of the optical fiber is
functionalized by dropcasting a droplet of 20 .mu.l of a monomer
solution on an asymmetric microlens array replica (or, in some
instances, master) and a silanized optical fiber tip was contacted
with the droplet and cured for 60 min, in accordance with one or
more embodiments of the present invention.
[0015] FIGS. 9A-9E relate to the interrogation of an
alcohol-responsive hydrogel sensor attached chemically to a glass
slide, showing (A) a schematic diagram of the setup utilized to
interrogate the sensors which included a laser pointer, a sample
holder, and a power meter; (B)-(D) graphical views of the spatial
optical profile of the transmitted diffused light beam from the
alcohol-responsive hydrogel based sensor while the sensor was
tested in ethanol, propan-2-ol, and DMSO, respectively; and (E) a
graphical view showing the maximum transmitted power (P.sub.t) of
the laser beam passing through the alcohol-responsive hydrogel
based sensor submerged in various alcohol concentrations, in
accordance with one or more embodiments of the present
invention.
[0016] FIGS. 10A-10I relate to the interrogation of a fiber optic
probe for alcohol sensing in a transmission configuration and a
reflection configuration, showing (A) a schematic of the setup
utilized to investigate the fiber optic probe's response in
transmission mode, with the setup including fiber probe coupled to
a laser pointer at one end and the alcohol-responsive hydrogel
sensor attached to the end of the optical fiber was soaked in an
alcohol solution container placed over a photodetector or a
smartphone; (B)-(C) microscopic images of a multimode silica fiber;
(D) photographs of a silica fiber with a hydrogel sensor attached
to an end thereof guiding different monochromatic light beams; (E)
graphical views showing the maximum optical transmitted power
(P.sub.t) from the fiber optic probe versus alcohol concentrations
while said probe was illuminated with a green laser (532 nm) and
the output signals were recorded with an optical power meter; (F) a
graphical view showing the illuminance of the fiber optic probe
detected by a smartphone while the probe was submerged in various
alcohol concentrations recorded and illuminated by a white light
source; (G) a schematic of the setup utilized to investigate the
fiber optic probe in reflection mode, where the fiber optic probe
was coupled with a white light source and a power meter using a
2.times.1 coupler and where the coupler included seven optical
fibers, with one fiber illuminating the fiber optic probe and the
other six fibers guiding reflected light from the probe to the
power meter; (H) a graphical view showing reflected power through
the fiber optic probe versus alcohol concentrations; and (I) a
graphical view showing the maximum transmitted power (P.sub.t) of
the fiber optic probe tested in ethanol (5% v/v) and DI water for 6
cycles versus time, in accordance with one or more embodiments of
the present invention.
[0017] FIGS. 11A-11K relates to interrogation of the pH-responsive
hydrogel sensor attached chemically on a glass slide and the fiber
optic probe for pH sensing in a transmission configuration and a
reflection configuration, showing (A) a graphical view of the
spatial optical profiles of the transmitted diffused light passing
through the pH-responsive hydrogel sensor while the pH-responsive
hydrogel sensor was submerged in various pH solutions and
illuminated by a green laser beam, 532 nm at 24.degree. C.; (B) a
graphical view showing the maximum transmitted power for the beam
passing through the pH-sensor submerged in various pH solutions;
(C) a schematic diagram of the setup utilized for testing the
pH-responsive hydrogel sensor in reflection mode, where the sensor
was illuminated by a monochromatic beam (532 nm) and the reflected
signal was picked up by an optical power meter; (D) a graphical
view showing the maximum optical reflected power from the
pH-responsive hydrogel sensor exposed to various pH solutions and
illuminated by a green laser beam; (E) a schematic diagram of the
setup utilized for testing the fiber optic probe in transmission
mode; (F) a graphical view showing the maximum transmitted power of
the fiber probe recorded when the functionalized probe tip was
submerged in various pH solutions; (G) a graphical view showing the
maximum illuminance emitted from the fiber optic probe recorded by
a smartphone when the probe was submerged in different pH
solutions; (H) a graphical view showing the reflected power in the
fiber optic probe recorded by the optical power meter when the
fiber optic probe was soaked in various pH solutions; (I) a
graphical view showing kinetic swelling of the pH-responsive
hydrogel sensor when said hydrogel sensor was soaked in a pH 6.0
solution and P.sub.t was recorded; (J) a graphical view showing the
maximum transmitted power of the fiber tested in two different pH
solutions for 3 cycles versus time; (k) a graphical view showing
the reflected optical power in the biocompatible fiber probe when
it was submerged in various pH solutions, in accordance with one or
more embodiments of the present invention.
[0018] FIGS. 12A-12D are schematic diagrams showing (A) a method of
preparing a glass-constrained glucose-responsive hydrogel sensor
stamped with an asymmetric microlens array; (B)-(C) the
functionalization process of the silica and hydrogel optical
fibers; and (D) the fabrication process for the biocompatible
hydrogel fiber, in accordance with one or more embodiments of the
present invention.
[0019] FIGS. 13A-13F relate to the quantification of glucose
concentration by a glucose-responsive hydrogel sensor, showing (A)
a schematic diagram of the setup utilized for recording glucose
concentrations in transmission mode; (B) a graphical view showing
the profile of the optical transmitted power passing through the
sensor against glucose concentrations when the sensor was
illuminated by a green laser (532 nm); (C) a graphical view showing
the P.sub.t of the sensor at various glucose concentrations (0-50
mM), with the inset showing the glucose range of 0-20 mM; (D) a
schematic diagram of the setup utilized for interrogating the
glucose sensor in the reflection mode; (E) a graphical view showing
the maximum transmitted illuminance (L.sub.t) of the sensor versus
glucose concentrations while the sensor was illuminated by the
broadband white light beam, and the illuminance was recorded by an
ambient light sensor of a smartphone; and (F) a graphical view of
the P.sub.r of the hydrogel sensor for various glucose
concentrations captured in reflection mode, with the inset showing
the glucose concentrations range of 0-20 mM, in accordance with one
or more embodiments of the present invention.
[0020] FIGS. 14A-14I relate to detection of glucose using a
glucose-responsive hydrogel sensor attached to a silica optical
fiber in transmission mode, showing (A) a schematic diagram of the
setup utilized to test the functionalized fiber in transmission
mode; (B)-(C) optical microscopy images of the silica multimode
fiber; (D) photographs of the silica fiber optic probe coupled to
blue, green, and red lasers; (E) a graphical view showing the
maximum optical transmitted power (P.sub.t) of the functionalized
fiber submerged in various glucose concentrations over time; (F) a
graphical view showing the P.sub.t of the fiber against glucose
concentrations (0-50 mM), while the fiber optic probe was coupled
with a green laser and the readout was recorded by a power meter,
with the inset showing measurements for the glucose range of 5-20
m; (G) a graphical view showing the L.sub.t of the fiber optic
probe versus glucose concentrations where the fiber optic probe was
coupled to a green laser pointer and the readouts were captured by
an ambient light sensor of a smartphone, with the inset showing the
glucose concentration range of 5-20 mM; (H) a graphical view
showing the L.sub.t of the fiber optic probe versus glucose
concentrations while the fiber optic probe was coupled with a
broadband white light source and the output signals were captured
by an ambient light sensor of a smartphone, with the inset showing
the glucose concentration range of 5-20 mM; and (I) a graphical
view showing the P.sub.t of the fiber optic probe versus glucose
concentrations where the fiber optic probe was coupled with a
broadband white light source and the output signals were recorded
by an optical power meter, with the inset showing the glucose
concentration range of 5-20 mM, in accordance with one or more
embodiments of the present invention.
[0021] FIGS. 15A-15G relate to the silica fiber optic probe used
for glucose sensing in reflection mode, showing (A) a schematic
diagram of the setup utilized for interrogating the fiber optic
probe in the reflection configuration; (B) a graphical view showing
the optical reflected power versus the glucose concentrations while
the fiber optic probe was coupled with a white light source and the
output signal was captured by an optical power meter; (C) a
graphical view showing the maximum transmitted power of the fiber
optic probe over time at 10 mM glucose concentration; (D) a
graphical view showing the fiber optic probe's output signal versus
time at a glucose concentration of 10 mM for four cycles as the
green laser laser pointer coupled with the fiber optic probe and
the readings were recorded in transmission mode, the fiber optic
probe was reset in acetate buffer (pH 4.6), and the transmitted
power baseline was 611.+-.1 .mu.W and increased to 623.+-.1 .mu.W;
(E) a graphical view showing the lactate and glucose concentrations
versus the P.sub.t at human body temperature, 37.degree. C., the
test was carried out in transmission mode; (F) a graphical view
showing the solution's pH against the fiber optic probe's output
signal recorded in the transmission mode; (G) a graphical view
showing solution temperature versus the fiber optic probe's output
signals, the test was carried out in transmission mode, in
accordance with one or more embodiments of the present
invention.
[0022] FIGS. 16A-16D relate to stimuli-responsive hydrogel sensors,
showing (A) photographs of a fiber optic probe and a PEGDA hydrogel
cubes of various precursor concentrations; (B) a graphical view
showing the attenuation of green and red laser beams (532 and 650
nm) versus the precursor concentration (5-90 vol %); (C) a
graphical view showing the attenuation of the white light by the
hydrogels of 1 cm cube side versus the precursor concentrations;
(D) a graphical view showing testing relating to the biocompatible
functionalized fiber for glucose detection in the reflection
configuration, where the optical reflected power values were
recorded by the power meter versus glucose concentrations, in
accordance with one or more embodiments of the present
invention.
[0023] FIGS. 17A-17B show (A) an optical microscopic image of light
diffusing microstructures (an asymmetric microlens array)
replicated on a hydrogel surface and (B) a graphical view showing a
distribution of the light diffusing microstructures, in accordance
with one or more embodiments of the present invention.
[0024] FIG. 18 is a schematic diagram showing glucose-boron
complexation in a hydrogel matrix inducing a positive volumetric
shift, in accordance with one or more embodiments of the present
invention.
DETAILED DESCRIPTION
[0025] The present invention relates to fiber optic-integrated
light diffusers for sensing applications. More specifically, the
present invention relates to fiber optic probes that include light
diffusing microstructures imprinted on a stimuli-responsive
polymeric material that is attached to an end portion of an optical
fiber and can be used for sensing parameters. The fiber optic
probes disclosed herein can sense a wide variety of parameters with
high sensitivity and rapid response times, while also overcoming
many of the challenges and shortcomings of conventional fiber optic
probes in terms of fabrication, practicality, portability, and
readout methodology. For example, in addition to being reusable,
offering electromagnetic immunity, remote and implantable sensing
capabilities, miniaturization, and low volume samples, the fiber
optic probes of the present invention do not require high quality
films, coherent light sources, costly instrumentation, bulky
equipment, complex fabrication techniques, or output signal
processing. For example, some embodiments disclose a method of
fabricating fiber optic probes in which the sensor component is
synthesized, imprinted with light diffusing microstructures, and
attached to an optical fiber to form the fiber optic probe in a
single simple and easy step. The fiber optic probes thus avoid the
challenging steps involved in, for example, fabricating high
quality films, forming precisely shaped droplets as sensors, and
immobilizing a hydrogel on a thin metal layer.
[0026] As described above, the fiber optic probes of the present
invention generally comprise a sensor component attached to an end
of an optical fiber. The sensor component can include a
stimuli-responsive polymeric material imprinted with light
diffusing microstructures that form an asymmetric microlens array.
While not wishing to be bound to a theory, it is believed that the
light diffusing microstructures can modulate the incident angle of
reflected rays in the optical fiber. For example, in the presence
or absence of at least one stimulus, a polymeric material such as a
hydrogel can undergo a positive or negative volumetric shift that
alters the refractive index and the dimensions of the light
diffusing microstructures. A positive volumetric shift can, for
example, decrease the scattering angle of reflected rays in the
core of the optical fiber such that more rays satisfy the guidance
condition and remain confined in the fiber core. As a result, the
optical power from the fiber optic probe can undergo a change
(e.g., an increase or a decrease) in response to the stimulus and
this change in optical power can be correlated to the parameter(s)
being sensed, such as a pH level, analyte concentration, etc.
[0027] The versatility of the materials that can be used to form
the fiber optic probes and the wide range of parameters capable of
being sensed by these materials provides a high degree of
flexibility and tunability, and thus broadens the scope of sensing
applications in which the fiber optic probes can be used. For
example, embodiments describe fiber optic probes that can be used
in remote sensing and implantable biosensing applications.
Accordingly, the term sensing is used broadly herein and refers to
any type of sensing known in the art. For example, the fiber optic
probes can be used for sensing at least one parameter, detecting at
least one parameter, measuring at least one parameter, monitoring
at least one parameter, and so on. In addition, the parameters
capable of being sensed are not particularly limited, given that
sensor components such as stimuli-responsive hydrogels can be
customized (e.g., via the selection and combination of monomer
and/or crosslinker, relative amounts of monomer and/or crosslinker,
etc.) to sense a particular parameter (e.g., pH, etc.) or a
particular range of a parameter (e.g., pH levels between 5-7).
Parameters capable of being sensed by the fiber optic probes
disclosed herein include, for example and without limitation,
analytes, analyte concentrations, temperatures, pH levels, ionic
strength, wavelengths of light, ion concentrations, electric
fields, magnetic fields, solvents, pressures, and the like. For
example, the fiber optic probes can be used in remote or
implantable applications for continuous or intermittent real-time
quantitative sensing, monitoring, detecting, and/or measuring of
glucose, lactates, proteins, DNA, alcohols, metabolites,
biomarkers, pH (e.g., gastric pH), oxygen, compounds containing
oxygen such as metal oxides and/or metal hydroxides (e.g.,
rusting), carbon dioxide, in various aqueous solutions such as
human blood and/or plasma, among others.
[0028] Referring now to FIG. 1A, an isometric view of a fiber optic
probe 100 is shown, according to one or more embodiments of the
invention. The fiber optic probe 100 comprises an optical fiber 110
and a sensor component 120. The optical fiber 110 has a proximal
end 112 and a distal end 114. The sensor component 120 is attached
to the distal end 114 of the optical fiber 110 and includes a
stimuli-responsive polymeric material 122. Light diffusing
microstructures forming an asymmetric microlens array 124 can be
imprinted on the stimuli-responsive polymeric material 122 to
obtain the sensor component 120.
[0029] The optical fiber 110 and sensor component 120 can be
attached via various types of associative interactions. Examples of
associative interactions include, without limitation, chemical
interactions, physical interactions, and combinations thereof. In
some embodiments, the sensor component 120 is chemically attached
to the optical fiber 110. In some embodiments, the sensor component
120 is covalently bonded to the optical fiber 110. In some
embodiments, the sensor component 120 is attached to the optical
fiber 110 via hydrogen bonding. In some embodiments, the sensor
component 120 is attached to the optical fiber 110 via ionic
interactions. In some embodiments, the sensor component 120 is
attached to the optical fiber 110 via electrostatic dipole-dipole
interactions. In some embodiments, the sensor component 120 is
attached to the optical fiber 110 via van der Waal's forces. In
some embodiments, the sensor component 120 is attached to the
optical fiber 110 via one or more of covalent bonding, hydrogen
bonding, ionic interactions, electrostatic dipole-dipole
interactions, and van der Waal's forces, among other covalent and
noncovalent interactions.
[0030] The optical fiber 110 is not particularly limited. The
optical fiber 110 can include a core and the core can optionally be
surrounded by one or more layers, such as cladding, polymer
coatings, protective outer jackets, and the like, or the optical
fiber 110 can comprise or consist of a core, wherein the core can
comprise or consist of a polymeric material. Suitable optical
fibers 110 include single-mode optical fibers and multi-mode
optical fibers. For example, in some embodiments, the optical fiber
110 includes a multi-mode silica fiber. Other commercially
available optical fibers can also be used as the optical fiber 110.
In addition, the incompatibility of optical fibers, such as those
which are commercially available, with biological tissues can limit
their use in medical diagnostics due to the immune reactions in
vivo. Accordingly, in some embodiments, the optical fiber 110
comprises or consists of biocompatible polymeric materials, such as
hydrogels, formed in accordance with the methods disclosed herein.
Exemplary biocompatible polymeric materials include light-curable
and in particular UV-curable polymers and hydrogels, such as
certain stimuli-responsive hydrogels. For example, in some
embodiments, the optical fiber 110 comprises or consists of
polyethylene glycol diacrylate. In some embodiments, the optical
fiber 110 comprises or consists of polyethylene glycol diacrylate
(PEGDA) and 2-hydroxy-2-methylpropiophenone (2-HMP). In some
embodiments, the optical fiber 110 comprises a biocompatible
material, such as PEDGA and/or 2-HMP, and a low refractive index
material, such as calcium alginate, surrounding the biocompatible
core as biocompatible cladding.
[0031] Additional examples of polymeric materials that can be
included in the optical fibers 110 or used to form the optical
fibers 110 and/or biocompatible cladding include, without
limitation, natural or synthetic monomers, polymers, and
copolymers, as well as biocompatible monomers, polymers, and
copolymers. For example, in some embodiments, the optical fibers
110 and biocompatible cladding can include one or more of the
following: polystyrene, neoprene, polyetheretherketone (PEEK),
carbon reinforced PEEK, polyphenylene, polyetherketoneketone
(PEKK), polyaryletherketone (PAEK), polyphenylsulphone,
polysulphone, polyurethane, polyethylene, low-density polyethylene
(LDPE), linear low-density polyethylene (LLDPE), high-density
polyethylene (HDPE), polypropylene,
polyetherketoneetherketoneketone (PEKEKK), nylon, fluoropolymers
such as polvtetrafluoroethylene (PTFE or TEFLON.RTM.), TEFLON.RTM.
TFE (tetrafluoroethylene), polyethylene terephthalate (PET or
PETE), TEFLON.RTM. FEP (fluorinated ethylene propylene),
TEFLON.RTM. PFA (perfluoroalkoxy alkane), and/or polymethylpentene
(PMP), styrene maleic anhydride, styrene maleic acid (SMA),
polyurethane, silicone, polymethyl methacrylate, polyacrylonitrile,
poly (carbonate-urethane), poly(amylacetate), nitrocellulose,
cellulose acetate, urethane, urethane/carbonate, polylactic acid,
polyacrylamide (PAAM), poly(N-isopropylacrylamide)(PNIPAM),
poly(vinylmethylether), poly(ethylene oxide), poly(ethyl
(hydroxyethyl) cellulose), poly(2-ethyl oxazoline), polylactide
(PLA), polyglycolide (PGA), poly(lactide-co-glycolide) PLGA,
poly(.epsilon.-caprolactone), polydiaoxanone, polyanhydride,
trimethylene carbonate, poly(hydroxybutyrate), poly(ethyl
glutamate), poly(DTH-iminocarbonate), poly(bisphenol A
iminocarbonate), poly(orthoester) (POE), polycyanoacrylate (PCA),
polyphosphazene, polyethyleneoxide (PEO), polyethylene glycol (PEG)
or any of its derivatives, polyacrylacid (PAA), polyacrylonitrile
(PAN), polyvinylacrylate (PVA), polyvinylpyrrolidone (PVP),
polyglycolic lactic acid (PGLA), poly(hydroxypropylmethacrylamide)
(PHPMAm), polyvinyl alcohol (PVOH), PEG diacrylate (PEGDA),
poly(hydroxyethyl methacrylate) (PHEMA), N-isopropylacrylamide
(NIPA), polyoxazoline (POx), poly(vinyl alcohol)-poly(acrylic acid)
(PVOH-PAA), collagen, silk, fibrin, gelatin, hyaluron, cellulose,
chitin, dextran, casein, albumin, ovalbumin, heparin sulfate,
starch, agar, heparin, alginate, fibronectin, fibrin, keratin,
pectin, elastin, ethylene vinyl acetate, ethylene vinyl alcohol
(EVOH), polyethylene oxide, PLLA (poly(L-lactide) or poly(L-lactic
acid)), poly(D,L-lactic acid), poly(D,L-lactide),
polydimethylsiloxane (PDMS), poly(isopropyl acrylate) (PIPA),
polyethylene vinyl acetate (PEVA), PEG styrene,
polytetrafluoroethylene RFE such as TEFLON.RTM. RFE or KRYTOX.RTM.
RFE, fluorinated polyethylene (FLPE or NALGENE.RTM.), methyl
palmitate, poly(N-isopropylacrylamide) (NIPA), polycarbonate,
polyethersulfone, polycaprolactone, polymethyl methacrylate,
polyisobutylene, nitrocellulose, medical grade silicone, cellulose
acetate, cellulose acetate butyrate, polyacrylonitrile,
poly(lactide-co-caprolactone) (PLCL), and/or chitosan.
[0032] The dimensions of the optical fibers 110 can vary widely and
thus are not particularly limited. For example, the diameter of the
optical fiber 110 can vary from a few micrometers up to sizes on
the scale of millimeters, with the lengths capable of being similar
in scale or even larger. In some embodiments, for example, the
diameter of the optical fiber 110 is about 500 microns. In some
embodiments, the diameter of the optical fiber 110 is about 950
microns and about 5 cm in light. In some embodiments, the diameter
of the optical fiber 110 is about 1 mm. These shall not be limiting
as other dimensions can be utilized herein without departing from
the scope of the present invention.
[0033] As described above, the sensor component 120 includes an
array of light diffusing microstructures. In some embodiments, the
array 124 of light diffusing microstructures includes a plurality
of microlenses. For example, in some embodiments, the light
diffusing microstructures and/or the plurality of microlenses form
an asymmetric microlens array 124. At least one advantage of the
asymmetric microlens array 124 is that it can increase the active
area of the sensor component 120 and enhance the diffusion rate of
the analyte into the a polymeric and/or hydrogel matrix, thereby
shortening response times and/or improving sensitivity, among other
things. In some embodiments, an asymmetric microlens array 124 can
refer to a microlens array including a plurality of microlenses and
having at least one aspect which is nonuniform, or asymmetric. For
example, the term includes microlens arrays having at least two
microlenses which are different from each other in at least one
aspect. The aspect(s) in which the microlens array and/or
microlenses are nonuniform (e.g., different, asymmetric, etc.) is
not particularly limited and can include, for example and without
limitation, the distribution and/or arrangement of microlenses, the
spacing between microlenses, as well as the size, shape, and/or
surface topology of the microlenses.
[0034] For example, in some embodiments, the asymmetric microlens
array 124 includes microlenses which are nonuniformly spaced apart.
In some embodiments, the asymmetric microlens array 124 includes
microlenses which are arranged in a nonordered distribution. In
some embodiments, the asymmetric microlens array 124 includes
microlenses which are arranged in a nonperiod configuration. In
some embodiments, the asymmetric microlens array 124 includes
microlenses, or at least two microlenses, which differ in at least
one base dimension (e.g., length, width, diameter, etc.). In some
embodiments, the asymmetric microlens array 124 includes
microlenses, or at least two microlenses, which differ in base
geometry (e.g., shape). In some embodiments, the asymmetric
microlens array 124 includes microlenses, or at least two
microlenses, which differ in height. In some embodiments, the
asymmetric microlens array 124 includes microlenses, or at least
two microlenses, which have different side profiles (e.g.,
cross-sectional shape). In some embodiments, the asymmetric
microlens array 124 includes microlenses, or at least two
microlenses, which differ in surface topology.
[0035] In some embodiments, the asymmetric microlens arrays 124 can
include microlenses having other features. In some embodiments, the
asymmetric microlens array 124 includes one or more microlenses,
wherein each of the one or more microlenses can independently have
an aspherical or spherical surface. For example, in some
embodiments, the asymmetric microlens array 124 includes at least
one microlense having an aspherical surface. In some embodiments,
the asymmetric microlens array 124 includes at least one microlense
having a spherical surface.
[0036] In some embodiments, each microlense and/or its surface can
be concave, convex, plano-concave, plano-convex, convex-concave,
and/or concave-convex, where convex means outwardly facing, for
example, away from the optical fiber. In some embodiments, the
asymmetric microlens array 124 includes at least one microlense
having a convex aspherical surface. In some embodiments, the
asymmetric microlens array 124 includes at least one microlense
having a plano-convex aspherical surface. In some embodiments, the
asymmetric microlens array 124 includes at least one microlense
having a convex-concave aspherical surface. In some embodiments,
the asymmetric microlens array 124 includes at least one microlense
having a convex-concave aspherical surface. In some embodiments,
the asymmetric microlens array 124 includes at least one microlense
having a convex spherical surface. In some embodiments, the
asymmetric microlens array 124 includes at least one microlense
having a plano-convex spherical surface. In some embodiments the
asymmetric microlens array 124 includes at least one microlense
having a convex-concave spherical surface. In some embodiments, the
asymmetric microlens array 124 includes at least one microlense
having a convex-concave spherical surface.
[0037] In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a concave aspherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a plano-concave aspherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a concave-convex aspherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a concave-convex aspherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a concave spherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a plano-concave spherical
surface. In some embodiments the asymmetric microlens array 124
includes at least one microlense having a concave-convex spherical
surface. In some embodiments, the asymmetric microlens array 124
includes at least one microlense having a concave-convex spherical
surface.
[0038] In some embodiments, the asymmetric microlens array 124
includes one or more conical-shaped microlenses. In some
embodiments, the asymmetric microlens array 124 includes one or
more hemispherical-shaped microlenses. In some embodiments, the
asymmetric microlens array 124 includes one or more
aspherical-shaped microlenses. In some embodiments, the asymmetric
microlens array 124 includes one or more cylindrical-shaped
microlenses. In some embodiments, the asymmetric microlens array
124 includes hyperbolic-shaped microlenses. In some embodiments,
the asymmetric microlens array 124 includes one or more of
micro-spheres, micro-pikes, micro-pyramids, micro-grooves,
micro-cones, micro-peaks, micro-blocks, among others. In some
embodiments, the asymmetric microlens array 124 includes any one or
more of the foregoing and other features disclosed elsewhere
herein.
[0039] The light diffusing microstructures and, in particular, the
asymmetric microlens arrays 124 can be imprinted on a
stimuli-responsive polymeric material 122 to form the sensor
component 120. Exemplary stimuli-responsive polymeric materials 122
include light-curable stimuli-responsive hydrogels which can be
imprinted with an asymmetric microlens array 124 to form hydrogel
sensors 120. Other polymeric materials which can undergo a change
in at least one property in response to at least one stimulus can
also be utilized herein as the stimuli-responsive polymeric
material 122. Suitable polymeric materials include, for example and
without limitation, natural or synthetic polymers (e.g., hydrogels,
homopolymers, copolymers, terpolymers, polymer blends, etc.),
oligomers, monomers, and the like, such as those described above in
relation to the optical fibers. The change can include physical
changes, chemical changes, or both physical changes and chemical
changes. For example, the changes can include a change from
hydrophilic to hydrophobic (and vice versa), changes in color
and/or transparency, changes in conductivity, changes in
permeability, changes in shape, as well as reversible
conformational changes and/or physico-chemical changes, such as
folding/unfolding transitions, reversible precipitation behavior,
or other conformational changes. The at least one stimulus can
include at least one of temperature, pH, pressure, wavelength of
light, ionic strength, ion concentration, analyte concentration,
electric field, magnetic field, solvent, and the like. Examples of
stimuli-responsive polymeric materials include, without limitation,
temperature-responsive polymers, pH-responsive polymers,
light-responsive polymers, ion-responsive polymers,
analyte-responsive polymers (e.g., for sensing oxygen, carbon
dioxide, glucose, etc.), and the like. Additional examples of
polymers include, without limitation, block copolymers and graft
copolymers having one or more stimuli-responsive polymer
components. For example, a stimuli-responsive block copolymer can
include a temperature-sensitive polymer block. A stimuli-responsive
graft copolymer can include a pH-responsive polymer backbone or
pendant temperature-sensitive polymer components. the
stimuli-responsive polymeric materials can in addition or in the
alternative include any of the polymeric materials disclosed above
in the discussion regarding the optical fibers.
[0040] Referring now to FIG. 1B, an isometric view of the sensor
component 120 is provided to illustrate the asymmetric microlens
array 124 in more detail, according to one or more embodiments of
the invention. In the illustrated embodiment, the asymmetric
microlens array 124 is imprinted on a stimuli-responsive hydrogel
122 and includes a plurality of convex aspherical microlenses, such
as convex aspherical microlenses 126A, 126B, 126C. The plurality of
convex aspherical microlenses forming the asymmetric microlens
array 124 are arranged in a nonordered, nonperiodic configuration,
with nonuniform spacing between adjacent microlenses. Further, the
plurality of convex aspherical microlenses have nonuniform base
dimensions, nonuniform base geometries, and nonuniform heights. In
addition, the plurality of convex microlenses have nonuniform
surface topologies and side profiles. FIG. 1C is a side profile
view of a portion of the asymmetric microlens array 120 taken long
the line 1-1, illustrating various nonuniform shapes, side
profiles, heights, base dimensions, spacing between microlenses,
and surface topologies of microlenses, according to one or more
embodiments of the invention. While the microlenses shown in FIG.
1C include plano-convex microlenses, other configurations are
possible and thus shall not be limiting.
[0041] Referring now to FIGS. 2A-2J, side profile views of
generally plano-convex aspherical microlenses are shown to
illustrate the variation among the microlenses in terms of shapes
and surface topologies, according to one or more embodiments of the
invention. One or more of the aspherical microlenses shown in FIGS.
2A-2J can be imprinted on a stimuli-responsive polymeric material.
The side profile views presented in FIGS. 2A-2J are nonlimiting.
Microlenses can have side profiles other than those presented in
FIGS. 2A-2J. The side profile views shown in those figures were
presented to illustrate the variations and diversity of shapes and
surface topologies of microlenses which can be utilized herein.
[0042] Referring now to FIG. 3, a flowchart of a method of
fabricating a fiber optic probe is shown, according to one or more
embodiments of the invention. As shown in FIG. 3, the method 300 of
fabricating a fiber optic probe can comprise one or more of the
following steps: depositing 302 a polymeric precursor solution on a
substrate mold; contacting 304 an end portion of an optical fiber
with the deposited polymeric precursor solution; and exposing 306
at least the end portion of the optical fiber and the deposited
polymeric precursor solution to light. At least one advantage of
the present method, among others, is that the sensor component can
be synthesized (e.g., a hydrogel can be synthesized and/or
crosslinked), imprinted with light diffusing microstructures (e.g.,
an asymmetric microlens array), and attached to the end portion of
the optical fiber in a single step, such as step 306. Other
advantages are or will become apparent from the discussion below
and elsewhere herein.
[0043] In step 302, a polymeric precursor solution is deposited on
a surface of a substrate mold. The surface of the substrate mold
can be stamped or imprinted with the inverse structure of the
desired asymmetric microlens array. For example, in embodiments in
which the stimuli-responsive polymeric material is to be imprinted
with an asymmetric microlens array that includes a plurality of
convex microlenses, the surface of the substrate mold will include
a plurality of concave microlenses. The inverse structure is used
so that the resulting stimuli-responsive polymeric material has the
desired topology once it is peeled or released from the substrate
mold. Conversely, the structure can be imprinted with a plurality
of convex microlenses if the stimuli-responsive polymeric material
is to be imprinted with an asymmetric microlens array that includes
a plurality of convex microlenses. Accordingly, in some
embodiments, the substrate mold has a surface including an inverse
asymmetric microlens array.
[0044] Since the polymeric precursor solution, once polymerized,
will form the stimuli-responsive polymeric material of the sensor
component, the volume or amount of the polymeric precursor solution
to be deposited on the substrate surface can depend on the size
(e.g., the diameter) of the optical fiber. For example, the volume
of polymeric precursor solution to be deposited on the surface of
the substrate mold should be sufficient to form a
stimuli-responsive polymeric material that at least partially
covers, or preferably, substantially or completely covers, the end
or end portion of the optical fiber. Usually, an appropriate volume
of the polymeric precursor to be deposited is one that is
sufficient to cover the portion of substrate mold that forms the
asymmetric microlens array. Since the such volumes are usually not
relatively large volumes, the depositing can be performed by
pipetting or drop-casting the polymeric precursor solution onto the
substrate surface, although other similar techniques, like coating,
can be used. In addition, the volume or amount of the polymeric
precursor solution to be deposited can be adjusted to achieve a
desired thickness of the stimuli-responsive polymeric material
following polymerization. As an example, in some embodiments, about
20 .mu.L of the polymeric precursor solution is deposited on the
surface of the substrate mold.
[0045] As discussed above, the polymeric precursor solution
includes precursors that can be polymerized, crosslinked, and/or
cured to form the stimuli-responsive polymeric material. While any
of the polymeric materials disclosed herein and/or its precursors
can be used, in some embodiments, the polymeric precursor solution
includes precursors for light-curable stimuli-responsive hydrogels,
preferably UV-curable stimuli-responsive hydrogels. For example,
the polymeric precursor solution can include a light-curable
stimuli-responsive hydrogel precursor solution that includes one or
more of the following: at least one monomer, at least one
photoinitiator, at least one crosslinking agent, and at least one
functionalizing agent. Additional examples of components that can
be included in the precursor solution include, without limitation,
oligomers, macromers, prepolymers, coinitiators, stabilizers, and
plasticizers, among others. In some embodiments, these precursors
can be exposed to ultraviolet light to synthesize ultraviolet
light-curable (or UV-curable) stimuli-responsive hydrogels. In
other embodiments, precursors which are curable or crosslinked by
other means--such as X-rays, microwaves, .gamma.-radiation, thermal
treatments, and the like--can be utilized herein without departing
from the scope of the present invention. In addition, other
additives, such as pH adjusting agents, solvents, and wetting
agents, can optionally be further included in the polymeric
precursor solution.
[0046] In some embodiments, the polymeric precursor solution is a
hydrogel precursor solution that can be implemented herein to form
UV-curable stimuli-responsive hydrogels. In some embodiments, the
UV-curable stimuli-responsive hydrogel includes a
glucose-responsive hydrogel that can be used for glucose sensing.
For example, in some embodiments, the hydrogel precursor solution
includes acrylamide; N,N'-methylenebisacrylamide;
3-(acrylamido)-phenylboronic acid (3-APBA); and
2,2-dimethoxy-2-2phenylacetophenone (DMPA). In some embodiments,
the UV-curable stimuli-responsive hydrogel includes an
alcohol-responsive hydrogel that can be used for alcohol sensing.
For example, in some embodiments, the hydrogel precursor solution
includes 2-hydroxyethylmethacrylate (HEMA); ethylene glycol
dimethacrylate (EGDMA); and 2,2-dimethoxy-2-phenylacetophenone
(DMPA). In some embodiments, the UV-curable stimuli-responsive
hydrogel includes an alcohol-responsive hydrogel that can be used
for pH sensing. For example, in some embodiments, the hydrogel
precursor solution includes 2-hydroxyethylmethacrylate (HEMA);
ethylene glycol dimethacrylate (EGDMA); acrylic acid (AA); and
2,2-dimethoxy-2-phenylacetophenone (DMPA). In some embodiments, the
hydrogel precursor solution further includes 2-(dimethylamino)
ethyl methacrylate.
[0047] Other hydrogel precursor solutions can be used herein
without departing from the scope of the present invention. For
example, in some embodiments, the hydrogel precursor solution
includes monomers and/or prepolymers of polyvinyl alcohol,
polyvinyl pyrrolidone, a polyvinyl pyrrolidone/vinyl acetate
copolymer, a vinyl ether/anhydric maleic acid copolymer, an
isobutylene/anhydric maleic acid copolymer, a
methoxyethylene/anhydric maleic acid copolymer, a methacrylic
acid/butyl acrylate copolymer, alginate, hydroxyethyl methacrylate,
hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, ethyl cellulose, methyl cellulose, sodium
carboxymethyl cellulose, dextrans, polysaccharides, a carboxyvinyl
copolymer, polyethylene oxide, polyethylene glycol, polyacrylamide,
polyhydroxyethyl methacrylate, polydioxolane, polyacrylic acid,
sodium polyacrylate, polyvinyl acrylate, polyacryl acetate,
polyacrylamide, poly-N-vinyl pyrrolidinone, agarose, and polyvinyl
chloride.
[0048] In some embodiments, the hydrogel precursor solution
includes one or more of the following, optionally as
photoinitiators (e.g., ultraviolet initiators): phenylacetophenone,
2,2-dimethoxy-2-phenylacetophenone (DMPA), hydroxy dimethyl
acetophenone, 4,4'-bis(dimethylamino)benzyl, methylbenzoylformate,
diphenyl (2,4,6-trimethylbenzoyl)-phosphine oxide, phenyl
bis(2,4,6-trimethyl benzoyl), oxy-phenyl-acetic
acid-2-[2-oxo-2-phenyl-acetoxy-ethoxy]-ethyl ester,
oxy-phenyl-acetic acid-2-[2-hydroxy-ethoxy]-ethyl ester,
4-cyclopentadiene-1-yl)
bis[2,6-difluoro-3-(1-H-pyrrole-1-yl)phenyl]titanium,
2-acetylnaphthalene, 2-naphthalaldehyde, iodonium salt, dicyclic
acid derivatives, 9.10-anthraquinone, anthracene, pyrene,
aminopyrene, perylene, phenanthrene, phenanthrenequinone,
9-fluorenone, dibenzosuberone, curcumin, xanthone, thiomichler's
ketone, 2,5-bis(4-diethylaminobenzyllidene)cyclopentanone,
2-(4-dimethylamino-benzyllidene))-indan-1-one,
.alpha.-(4-dimethylaminobenzyllidene))ketone such as
3-(4-dimethylamino-phenyl)-1-indan-5-yl-propenone,
3-phenylthiophthalimide, N-methyl-3,5-di(ethylthio)-phthalimide,
N-methyl-3,5-di(ethylthio)-phthalimide, phenothiazine,
methylphenothiazine, N-phenylglycine, amines such as
triethanolamine and N-methyldiethanolamine,
ethyl-p-dimethylaminobenzoate, 2-(dimethylamino)ethylbenzoate,
2-ethylhexyl-p-dimethylaminobenzoate,
octyl-para-N,N-dimethylaminobenzoate,
N-(2-hydroxyethyl)-N-methyl-para-toluidine, butoxyethyl
4-dimethylaminobenzoate, 4-dimethyl aminoacetophenone,
triethanolamine, methyl di ethanol amine, dimethylaminoethanol,
2-(dimethylamino)ethyl benzoate, poly(propylene
glycol)-4-(dimethylamino)benzoate, michler's ketone,
1-hydroxy-cyclohexyl-phenyl-ketone,
2-hydroxy-2-methyl-1-phenyl-1-propanone,
2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone,
2-benzyl-2-(dimethylamino)-1-[4-(4-morpholinyl)phenyl]-1-butanone,
and
2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone.
[0049] In some embodiments, the hydrogel precursor solution
includes one or more of the following, optionally as
photoinitiators (e.g., ultraviolet initiators): benzophenone,
4-phenyl benzophenone, 4-methoxy benzophenone, 4,4'-dimethyl
benzophenone, 4,4'-dichlorobenzophenone,
4,4'-bis(dimethylamino)-benzophenone,
4,4'-bis(diethylamino)benzophenone,
4,4'-bis(methylethylamino)benzophenone,
4,4'-bis(p-isopropylphenoxy)benzophenone, 3,3'-dimethyl-4-methoxy
benzophenone, methyl-2-benzoylbenzoate,
4-(2-hydroxyethylthio)-benzophenone, 4-(4-tolylthio)benzophenone,
1-[4-(4-benzoyl-phenylsulfanyl)-phenyl]-2-methyl-2(toluene-4-sulfonyl)-pr-
opane-1-one, 4-benzoyl-N,N,N-trimethylbenzenemethanaminium
chloride,
2-hydroxy-3-(4-benzoyl-phenoxy)-N,N,N-trimethyl-1-propaneaminium
chloride monohydrate,
4-(13-acryloyl-1,4,7,10,13-pentaoxatridecyl)-benzophenone, and
4-benzoyl-N,N-dimethyl-N-[2-(1-oxo-2-prophenyl)oxy]ethyl-benzenemetha-
naminium chloride.
[0050] In some embodiments, the hydrogel precursor solution
includes one or more of the following, optionally as crosslinking
agents: ethylene glycol dimethacrylate (EGDMA), benzyl
methacrylate, lauryl methacrylate, isodecyl methacrylate, phenoxy
methacrylate, 2-hydroxyethyl methacrylate, tetrahydro furfuryl
methacrylate, cetyl(C16) methacrylate, stearyl methacrylate,
methoxyPEG500 methacrylate, methoxyPEG600 methacrylate,
methoxyPEG1000 methacrylate, 1,6-hexandiol dimethacrylate,
butadiene dimethacrylate, neopentylglycol dimethacrylate,
ethyleneglycoldimethacrylate, diethyleneglycol dimethacrylate,
triethyleneglycol dimethacrylate, tetraethyleneglycol
dimethacrylate, bisphenol A(EO)4 dimethacrylate, bisphenol A(EO)3
dimethacrylate, bisphenol A(EO)10 dimethacrylate, bisphenol A(EO)30
dimethacrylate, 1,3-butyleneglycol dimethacrylate, polyethylene
glycol 400 dimethacrylate, polyethylene glycol 200 dimethacrylate,
PPG1000(EO)15 dimethacrylate, PPG1000(EO)3 dimethacrylate,
trimethylolpropane trimethacrylate, benzyl acrylate, lauryl
acrylate, isodecyl acrylate, phenol(EO) acrylate, phenol(EO)2
acrylate, phenol(EO)4 acrylate, phenol(EO)6 acrylate, tetrahydro
furfuryl acrylate, nonyl phenol(EO)4 acrylate, nonyl phenol(EO)8
acrylate, nonyl phenol(EO)2 acrylate, ethoxyethoxy ethyl acrylate,
stearyl acrylate, 1,6-hexandiol diacrylate, 1,6-hexandiol(EO)
diacrylate, butanediol diacrylate, hydroxy pivalic acid neopentyl
glycol diacrylate, tripropylene glycol diacrylate, dipropylene
glycol diacrylate, bisphenol A(EO)4 diacrylate, bisphenol A(EO)3
diacrylate, tricyclodecane dimethanol diacrylate, tetraethylene
glycol diacrylate, polyethylene glycol 400 diacrylate, polyethylene
glycol 200 diacrylate, polyethylene glycol 300 diacrylate,
polyethylene glycol 600 diacrylate, polypropylene glycol 400
diacrylate, polypropylene glycol 750 diacrylate, bisphenol A(EO)10
diacrylate, bisphenol A(EO)30 diacrylate, tris(2-hydroxy
ethyl)isocyanurate diacrylate, trimethylolpropane triacrylate,
trimethylolpropane(EO)3 triacrylate, trimethylolpropane(EO)6
triacrylate, trimethylolpropane(EO)9 triacrylate,
trimethylolpropane(EO)15 triacrylate, glycerin propoxylated
triacrylate, pentaerythritol triacrylate, trimethylolpropane(PO)3
triacrylate, tris(2-hydroxy ethyl)isocyanurate triacrylate,
pentaerythritol n-EO tetraacrylate, pentaerythritol tetraacrylate,
dipentaerythritol pentaacrylate, dipentaerythritol hexaacrylate,
caprolactone acrylate, O-phenylphenol EO acrylate, and methylene
bisacrylamide.
[0051] In some embodiments, the hydrogel precursor solution
includes one or more of the following, optionally as
functionalizing agents and molecular recognition agents:
phenylboronic acids and derivatives thereof, aptamers including
oligonucleotides and peptide molecules, and other chelating agents
for sensing a wide range of analytes, including biomolecules such
as proteins, DNR, and RNA. Non-limiting examples of such
functionalizing agents include, without limitation,
3-(acrylamido)-phenylboronic acid (3-APBA), 3-aminophenylboronic
acid, 5-amino-2-fluorophenylboronic acid,
4-amino-3-fluorophenylboronic acid, peptides, antibodies,
concanavalin A, glucose oxidase, glucose dehydrogenase, hexokinase,
glucose/galactose-binding protein, a protein and/or a fragment
functionally equivalent to a protein, a mutant of hexokinase, a
mutant of glucose/galactose-binding protein, a borate ester
derivative, and the like.
[0052] In some embodiments, the sensitivity and/or response time of
the hydrogel sensor and thus of the fiber optic probe can be
modulated by varying at least one of the following: the content of
the crosslinking agent (e.g., to tune the elasticity of the
resulting hydrogel sensor), the content of at least one monomer
(e.g., to tune selectively the sensing range), and the content of
the at least one photoinitiator. For example, the amount of the
crosslinking agent included in the hydrogel precursor solution can
range from greater than 0% by weight to about 80% by weight, or any
incremental value or subrange between that range. In some
embodiments, the amount of the monomer included in the hydrogel
precursor solution can range from about 0 to about 80% by weight,
or any incremental value or subrange between that range. In some
embodiments, the amount of photoinitiator included in the hydrogel
precursor solution can range from about 0% to about 80% by weight,
or any incremental value or subrange between that range. Unless
otherwise provided, all percentages by weight are based on the
total weight of the solution. In some embodiments, the sensitivity
and/or responsive time of the hydrogel sensor can be modulated by
including an additional monomer to form a copolymer.
[0053] In step (b), an end portion of the optical fiber is
contacted with the deposited polymeric precursor solution. For
example, in some embodiments, an end portion of an optical fiber is
contacted with a light-curable stimuli-responsive hydrogel
precursor solution deposited on the substrate mold. The contacting
can be performed by bringing the end portion of the optical fiber
and at least a portion of the deposited polymeric precursor
solution into physical contact, or immediate or close proximity.
The contacting should be sufficient to permit attachment of the
hydrogel sensor to the end of the optical fiber following step (c).
Any of the optical fibers of the present disclosure can be utilized
herein. For example, in some embodiments, the optical fiber is a
biocompatible fiber. In some embodiments, the optical fiber is a
UV-curable biocompatible fiber formed in accordance with the
methods disclosed herein as described in more detail below. In some
embodiments, the end portion of the optical fiber is silanized
prior to being contacted with the deposited polymeric precursor
solution. The silanized end of the optical fiber can be used to
form covalent bonds between the optical fiber and the
stimuli-responsive hydrogel. In some embodiments, crosslinking
agents are utilized to attach the stimuli-responsive hydrogel and
the optical fiber.
[0054] In step (c), the end portion of the optical fiber and the
deposited polymeric precursor solution are exposed to light. Any
wavelength of light suitable for carrying out the polymerization
can be utilized herein. For example, in some embodiments, the end
portion of the optical fiber and the deposited polymeric precursor
solution are exposed to ultraviolet light. The duration of the
exposure to light generally and in particular to ultraviolet light
is not particularly limited. For example, in some embodiments, the
exposure duration or cure duration is about 5 minutes. In some
embodiments, the exposure duration or cure duration is about 60
minutes. In some embodiments, the exposure duration or cure
duration is at least about 5 or about 15 seconds or longer. Other
wavelengths of light can be utilized herein. For example, in some
embodiments, the wavelengths of light used for curing include,
without limitation, gamma-radiation, X-rays, microwaves, etc.
Alternatively, in some embodiments, the end portion of the optical
fiber and the deposited polymeric precursor solution can be exposed
to a heat treatment, among other treatments, to carry out the
polymerization.
[0055] As described above, the surface of the substrate mold can
include the inverse structure of the asymmetric microlens array
that is to be imprinted on the stimuli-responsive polymeric
material and used as the sensor component of the fiber optic probe.
For example, in some embodiments, the substrate mold has a surface
including an inverse asymmetric microlens array. In some
embodiments, the substrate mold is replica diffuser, wherein the
inverse structure of the asymmetric microlens array formed on the
surface of the substrate mold is replica molded from a master light
diffuser.
[0056] For example, FIG. 4 is a flowchart of a method of
fabricating a replica diffuser (e.g., the substrate mold) from a
master light diffuser, according to one or more embodiments of the
invention. As shown in FIG. 4, the method can comprise depositing
402 a light curable prepolymer solution on a master light diffuser.
The master light diffuser can include a master asymmetric microlens
array, which can be used as a template or mold to form the inverse
asymmetric microlens array on the substrate mold. The depositing
can be performed by drop-casting, pipetting, or coating the light
curable prepolymer solution on the master light diffuser. The light
curable prepolymer solution can include one or more of oligomers,
monomers, photoinitiators, coinitiators, crosslinking agents,
stabilizers, and plasticizers, including any of those disclosed
herein. Usually, the prepolymer solution should be selected such
that the resulting polymer is one which can be used as a replica
diffuser without adverse interactions with the stimuli-responsive
polymeric material. For example, the prepolymer solution should be
selected such that, when the replica diffuser is used to imprint an
asymmetric microlens array on a stimuli-responsive polymeric
material, the resulting sensor component can be released or peeled
from the replica diffuser without causing any damage thereto. This
can be achieved by selecting materials which will not strongly bind
or irreversibly bind with stimuli-responsive polymeric materials
(e.g., by selecting materials that do not bind or at least
reversibly bind with materials used to form the sensor component).
In some embodiments, the light curable prepolymer solution is
ultraviolet light curable. For example, UV curable acrylics, such
acrylated epoxies, acrylated polyesters, acrylated urethanes,
acrylated silicones, and the like, can be utilized herein. Other
light curable polymeric materials can be used, including those
described elsewhere herein. In step 404, the light curable
prepolymer solution is exposed to light to cure the prepolymer
(e.g., cause polymerization therein). In step 406, the cured
polymer is released or peeled from the master light diffuser to
obtain the substrate mold (or replica diffuser) including the
inverse asymmetric microlens array. In some embodiments, the
releasing or peeling in step 406 can involve the use of a solvent.
In some embodiments, mechanical separation is sufficient to
separate the substrate mold from the master light diffuser.
[0057] Referring now to FIG. 5, a flowchart of a method of
fabricating an optical fiber is provided, according to one or more
embodiments of the invention. As shown in FIG. 5, the method 500
can comprise injecting 502 a light curable prepolymer solution into
a tubular body; exposing 504 the light curable prepolymer solution
to light to cure the prepolymer (e.g., to cause polymerization
therein); and extracting 506 a polymerized optical fiber from the
tubular body. Any of the light curable polymeric materials and
precursors of light curable polymers of the present disclosure can
be utilized herein. In some embodiments, precursors of ultraviolet
light curable polymers are injected into the tubular body. In some
embodiments, the light curable prepolymer solution includes
prepolymers or precursors of an ultraviolet light curable polymer
that is biocompatible and thus form biocompatible optical fibers.
For example, in some embodiments, the optical fiber is a
biocompatible hydrogel fiber. In some embodiments, the optical
fiber is a biocompatible polymeric fiber. In some embodiments, the
polymerized optical fiber is extracted in step 506 by applying
water pressure. In some embodiments, the polymerized optical fiber
is extracted in step 506 by applying air pressure. Other gases and
liquids can be utilized herein for extracting the polymerized
optical fiber and thus these examples shall not be limiting. In
some embodiments, the method 500 further comprising forming one or
more layers surrounding the polymerized optical fiber. For example,
in some embodiments, the layer has a lower refractive index than
the polymerized optical fiber and thus can be used as cladding.
[0058] Referring now to FIG. 6, a schematic diagram of a system 600
configured for operation in transmission mode is shown, according
to one or more embodiments of the invention. In the illustrated
embodiment, the system 600 includes a fiber optic probe 602. A
proximal end 604 of the fiber optic probe 602 is coupled to a light
source 608 which can be configured to transmit either monochromatic
light or broadband light through the fiber optic probe 602. A
distal end portion 606 of the fiber optic probe 602 includes a
sensor component 610 which as described above includes an
asymmetric microlens array imprinted on a stimuli-responsive
polymer. A light detector 612 is disposed proximally to the distal
end portion 606 of the fiber optic probe 602 such that at least a
portion of the light transmitted from the asymmetric microlens
array is incident upon the light sensor 612. Advantageously, an
optical power meter or a smartphone can be used as the light sensor
612. During operation, the distal end portion 606 of the fiber
optic probe 602 comprising the sensor component 610 can be exposed
to an environment 614 and the maximum optical transmitted power
recorded by the light sensor 612 can be correlated to the property
being sensed.
[0059] Referring now to FIG. 7, a schematic diagram of a system 700
configured for operation in reflection mode is shown, according to
one or more embodiments of the invention. In the illustrated
embodiment, the system 700 includes a fiber optic probe 702. A
proximal end 704 of the fiber optic probe 702 is coupled to a light
source 708 via a first terminal 709 (e.g., an input terminal) of a
coupler 707 and to a light sensor 712, such as an optical power
meter, via a second terminal 713 (e.g., an output terminal) of the
coupler 707. The coupler 707 can include a plurality of optical
fibers, at least one of which is used for transmitting light from
the light source 708 and one or more of which is used for guiding
reflected light to the light sensor 712. A distal end portion 706
of the fiber optic probe 702 includes a sensor component 710, the
sensor component 710 having an asymmetric microlens array imprinted
on a stimuli-responsive polymeric material. During operation, the
distal end portion 706 of the fiber optic probe 702 comprising the
sensor component 710 can be exposed to an environment 714 and the
maximum optical reflected power recorded by the light sensor 712
can be correlated to the property being sensed.
[0060] In some embodiments, a system is provided, wherein the
system comprises a fiber optic probe including an optical fiber and
a stimuli-responsive material, wherein the stimuli-responsive
material has a first surface attached to the optical fiber and a
second surface patterned with an asymmetric microlens array; a
light source coupled to the fiber optic probe, wherein the light
source is configured to transmit light through the optical sensor;
and a light sensor for detecting light transmitted through the
asymmetric microlens array or light reflected from the asymmetric
microlens array.
[0061] In some embodiments, a system is provided, the system
comprising a fiber optic probe including an optical fiber and a
sensor component attached to the optical fiber, the sensor
component including an asymmetric microlens array imprinted on a
stimuli-responsive hydrogel; a light source coupled to the fiber
optic probe, wherein the light source is configured to transmit
light through the optical sensor; and a light sensor for detecting
light transmitted through the asymmetric microlens array or light
reflected from the asymmetric microlens array.
[0062] According to one or more embodiments, fiber optic probes
comprising alcohol-responsive hydrogel sensors are provided. The
fiber optic probes disclosed herein can be used for determining the
volumetric modulation of stimuli-responsive polymers in real time.
Asymmetric microlens structures (light diffusing microstructures)
were imprinted on alcohol-responsive hydrogels during a UV curing
process and used as stand-alone hydrogel sensors or chemically
attached to the ends of silica and biocompatible optical fibers to
form fiber optic probes. (FIGS. 8A-8C). Quantitative measurements
were carried out using a smartphone to demonstrate the ease,
simplicity, and practicality of the readout methodology. To
demonstrate the utility in real-time sensing, the fiber optic probe
was evaluated in various concentrations of ethanol, propan-2-ol,
and dimethyl sulfoxide. To develop biocompatible probes for
physiological applications, an asymmetric microlens array-imprinted
polymer was attached to the end of a hydrogel optical fiber. The
developed hydrogel fiber probes may have application in
point-of-care diagnostics, continuous biomarker monitoring, and
critical care sensing devices.
[0063] The stand-alone alcohol sensor was constrained on a glass
slide and was evaluated in solutions having alcohol concentrations
ranging from 0-50 vol %. The stand-alone sensor was equilibrated in
DI water before testing and solutions containing various
concentrations of ethanol, propan-2-ol, and DMSO were prepared. The
sensor was submerged in DI water (1 ml) and was illuminated with a
green laser of wavelength 532 nm (FIG. 9A). The spatial profile of
the optical transmitted power (S.sub.t) was recorded by an optical
power meter and was taken as the reference. The DI water was
replaced with an aqueous ethanol solution (2 vol %, 1 ml), and the
S.sub.t was recorded again. The ethanol solution (2 vol %) was
replaced by higher ethanol concentration (4 vol %), and the reading
was recorded; this protocol was repeated until reaching an alcohol
concentration of 50 vol % (FIG. 9B). The same procedure was
followed to examine the sensor's sensitivity to propan-2-ol and
DMSO.
[0064] The optical transmitted power from the sensor exhibited a
Gaussian profile. An increase in the maximum optical transmitted
powers (P.sub.t) was observed with increasing alcohol
concentration. While not wishing to be bound to a theory, it is
believed that this trend was observed due to decreasing scattering
angles resulting from decreasing the diffusion efficiency of the
microlens structures, thereby concentrating the transmitted power
on a smaller solid angle and thus leading to a smaller circular
area on the projection screen/photodiode sensor (FIGS. 9B-9D). The
P.sub.t readings as a practical readout method were utilized to
monitor the alcohol concentrations. The sensor responded to all the
presented alcohols; however, it was more sensitive to DMSO as
compared to propan-2-ol and ethanol, this was likely due to DMSO
penetrating the hydrogel network (FIG. 9E). For example, the
ability of an alcohol to penetrate and/or diffuse into a hydrogel
matrix can increase when the alkyl chain length increases. The
sensor's response to ethanol was nonlinear, with a sensitivity of
.about.4 .mu.W vol %.sup.-1 for low ethanol concentrations in the
range of 0-10 vol %, which increased to .about.6 .mu.W vol %.sup.-1
for higher concentrations in the range of 10 to 40 vol %, and
reached .about.20 .mu.W vol %.sup.-1 for ethanol concentrations in
the range of 40-50 vol % (FIG. 9E). Further, the sensor's response
to propan-2-ol was linear, with a sensitivity of .about.7.3 .mu.W
vol %.sup.-1 observed across the entire concentration range of 0-50
vol %. In addition, the sensor's response to DMSO was nonlinear for
the entire tested concentration range (0-50 vol %). The sensitivity
increased from .about.8 .mu.W vol %.sup.-1 for concentrations in
the range of 0-10 vol %, to .about.12 .mu.W vol %.sup.-1 for
concentrations in the range of 10-40 vol %, and to .about.13 .mu.W
vol %.sup.-1 for higher concentrations in the range of 40-50 vol %
(FIG. 9E). The sensitivity of the hydrogel to alcohols could be
controlled by varying the content of the cross linker; hence, the
elasticity of the hydrogel film could be tuned. Unlike diffraction-
and chromophore-based systems, the asymmetric microlens-based
sensors disclosed herein were able to cover the entire alcohol
concentration range 0-50 vol %.
[0065] For the remote sensing applications, the alcohol hydrogel
sensor was chemically attached to an end of a multimode silica
fiber having a diameter of 500 .mu.m. The fabrication of the fiber
optic probe included preparing a poly HEMA matrix which is an
alcohol-responsive polymer, replicating the asymmetric microlens
arrays, and attaching the hydrogel sensor to the end of the optical
fiber. Advantageously, the fabrication was achieved in one step via
a simple process. Unlike fiber optic probes based on Surface
Plasmon resonance (SPR) or the interferometric spectroscopy, the
fabrication process for the fiber optic probes disclosed herein was
facile and rapid. Additional advantages of the fabrication
processes disclosed herein are that a multitude of complicated
steps can be avoided, such as pretreatment of the optical fiber,
depositing a thin metal layer (plasmonic coating), immobilizing the
hydrogel on the metal layer, and other stringent requirements such
as the need for high-quality films.
[0066] The fiber optic probe was tested for alcohol detection in
the transmission and reflection configurations. Optical microscope
images of the silica fiber and photos of the fiber probe guiding
different laser beams are displayed in FIGS. 10B-10D. A green laser
(532 nm) was coupled with the functionalized silica fiber and the
output signals (P.sub.t) were recorded by an optical power meter or
a smartphone (FIG. 10A). Upon increasing the alcohol concentration,
the probe exhibited a linear response to propan-2-ol and nonlinear
responses to ethanol and DMSO. All results were consistent with the
results discussed above involving the sensor constrained on a glass
substrate. The fiber optic probe exhibited a higher sensitivity to
DMSO than to propan-2-ol and ethanol. Starting from the identical
P.sub.t values of 390 .mu.W at 0 vol %, the P.sub.t recorded by the
optical power meter showed an increase of .about.246, 273, and 500
.mu.W at 50 vol % concentrations of ethanol, propan-2-ol, and DMSO,
respectively (FIG. 10E). Similarly, the maximum transmitted
luminance (L.sub.t) recorded by the smartphone showed an increase
of .about. 181, 202, and 370 Lux at 50 vol % concentrations of
ethanol, propan-2-ol, and DMSO, respectively (FIG. 10F). Output
signal trends recorded by the smartphone and the optical power
meter were analogous, confirming the reliability of the
smartphone-based readout method. One of the multitude of advantages
of the fiber optic probes disclosed herein is that they permit a
simple and direct readout process that does not require complex
data processing, expensive and bulky instrumentation, like
computers. The fiber optic probes disclosed herein are compact and
simple. Additionally, the fiber optic probes reduce the cost of the
sensor by introducing cost-effective and portable instruments for
recording the output signals (e.g., a smartphone can be used).
Further advantages of the fiber optic probes include their low
limit of detection (2%, v/v) compared with conventional fiber optic
probes that depend on interferometry, Surface Plasmon resonance,
Fresnel reflectometry, and total internal reflection phenomena. For
instance, tapered fiber probe exhibit a LOD of 5% (v/v) for
ethanol; Fabry-Periot fiber probes exhibit a LOD of 10% (w/w) for
ethanol; fiber probes based on Surface Plasmon resonance exhibit a
LOD of 10% (v/v); and fiber probes based on Fresnel reflectometry
principal exhibit a LOD of 30% (v/v) for ethanol. Alcohol fiber
probe based on the change in the total internal reflection
exhibited higher LOD of 10% (v/v). Even colorimetric-responsive
hydrogels based on inverse opal structure made of the same
alcohol-responsive hydrogel (HEMA) showed LOD of 5% (v/v) for
ethanol detection.
[0067] For implantable biosensing applications, the fiber optic
probes were used in systems configured to operate in reflection
mode. A broadband white light source was coupled to one of the
terminals at the bifurcated side of a 2.times.1 coupler and the
reflected power was collected from the second terminal at the same
side using an optical power meter (FIG. 10G). The functionalized
end of the probe was submerged in various alcohol concentrations.
With increasing alcohol concentration, the hydrogel functionalized
tip underwent a positive dimensional shift which increased the
reflected power guided in the probe. At 50 vol % ethanol,
propan-2-ol, and DMSO concentrations, maximum increases of
.about.0.7, 1, and 1.6 .mu.W were recorded, respectively (FIG.
10H). The trend of the output signals in the reflection
configuration was comparable to the trend in the transmission
configuration as the response of the fiber probe was linear for
propan-2-ol and nonlinear for ethanol and DMSO, in addition to the
highest sensitivity being observed for DMSO and the lowest for
ethanol. The reusability of the fiber probe was examined by
exposing the fiber probe to ethanol solution (5%, v/v) for six
cycles (FIG. 10I). The fiber probe was modulated over several
cycles with limited random memory retention. The response time was
short, within a few seconds, and the equilibrium time was about 60
seconds, which varied depending on the alcohol type and alcohol
concentration.
[0068] Continuous monitoring of pH levels in blood and brain tissue
of critically ill patients and patients suffering from a traumatic
brain injury is a primary medical exigency. The pH levels of the
brain can indicate tissue viability and decreases during brain
insult from the normal pH 7.4 to 6.8. Additionally, continuous
monitoring of the brain tissue pH might be useful in the treatment
of comatose neurosurgical patients. While electrochemical sensors
have been developed, hydrogel-based fiber optic probes may present
unique advantages over electrochemical sensors as they are
biocompatible for in vivo sensing and safer given that no
electrical current is passed.
[0069] According to one or more embodiments, fiber optic probes
comprising pH-responsive hydrogel sensors are provided. The fiber
optic probes disclosed herein can be used for determining the
volumetric modulation of stimuli-responsive polymers in real time.
Asymmetric microlens structures (light diffusing microstructures)
were imprinted on pH-responsive hydrogels during a UV curing
process and used as stand-alone hydrogel sensors or chemically
attached to the ends of silica and biocompatible optical fibers to
form fiber optic probes. (FIGS. 8A-8C). Quantitative measurements
were carried out using a smartphone to demonstrate the ease,
simplicity, and practicality of the readout methodology. To
demonstrate the utility in real-time sensing, the fiber optic probe
was evaluated in solutions having varying pH levels. The fiber
probe showed a rapid response to pH in the acidic region with a
sensitivity of 40 nW pH.sup.-1. To develop biocompatible probes for
physiological applications, a microlens array-imprinted polymer was
attached to the tip of a hydrogel optical fiber. The optical fiber
probe in the refection configuration showed a sensitivity of 7 nW
pH.sup.-1. The developed hydrogel fiber probes may have application
in point-of-care diagnostics, continuous biomarker monitoring, and
critical care sensing devices.
[0070] Asymmetric microlens structures (light diffusing
microstructures) were imprinted on pH responsive-hydrogels during a
UV curing process to create stand-alone and fiber integrated
sensors (FIGS. 8A-8C). The stand-alone hydrogel pH sensor imprinted
with the asymmetric microlens array and constrained on a glass
slide was tested in transmission mode in various pH solutions
(4.3-8.8) of ionic strength (150 mM) at 24.degree. C. The sensor
was submerged in pH solution (1 ml) and was illuminated with a
laser beam (532 nm) and S.sub.t was recorded by an optical power
meter. The sensor's volume experienced a positive shift with
increasing pH of the solution due to the Donnan's potential
resulting from ionization of the carboxyl group and dissolving of
the carboxylates. Accordingly, the light diffusing efficiency of
the sensor decreased, thus increasing P.sub.t on account of the
forward scattering angle (FIG. 11A). Initially, the pH sensor
significantly responded to pH level in the range of 5.0 to 7.0,
with responses hard to detect in the alkaline region, where the
output signal increased by .about.1.7 .mu.W (40%), as it increased
from 4.2 .mu.W to 5.9 .mu.W upon increasing pH from 5.0 to 7.0
(FIG. 11B). When the pH was changed from 4.3 to 5.0, the sensor's
output signal changed by .about.8%, consistent with the pH sensor
based on poly HEMA. The hydrogel pH sensor showed a similar
response in the reflection mode as compared with the transmission
mode, where the output signal significantly increased by .about.19%
with increasing pH from 5.0 to 7.0, and no response was recorded
above pH 7.0 (FIG. 11D). The output signal changed by 1.5% when pH
was increased from 4.3 to 5.0. The decrease of the sensor's
sensitivity in the reflection mode was be attributed to the readout
setup, where the sensor was illuminated at 45.degree. and the
detector was fixed at the same angle (FIG. 11C).
[0071] The hydrogel sensor was chemically attached to the tip of a
silica optical fiber following the same protocol utilized to attach
the alcohol sensor. The sensing investigations were carried out in
both transmission and reflection modes (FIG. 11E). The response of
the fiber optic probe to pH was comparable to the response of the
constrained pH hydrogel sensor attached to the glass substrate
(FIG. 11F). The trends of the output signals recorded by the
smartphone and the power meter were same (FIGS. 11F-11G). The fiber
optic probe was very sensitive in the pH range from 5.0 to 7.0 and
displayed negligible response above pH 7.0. The recorded L.sub.t by
the smartphone showed a change of .about.40% upon changing the pH
from 5.0 to 7.0, where a .about.2% output change corresponded to a
0.1 pH increment. The response of the pH fiber probe in the
reflection configuration was analogous to the transmission mode
(FIG. 11H). An increase of 115 nW was measured in the output signal
upon increasing the pH from 5.0 to 7.0, with the sensitivity of
.about.57 nW pH.sup.-1. The fiber optic probe can be used for
monitoring gastric pH which has a physiological range of 1-7, and
for milk quality application as the milk pH lies in the range of
4.6-6.7. The fiber optic probes can be utilized in other
applications, as the sensitivity of the fiber probe and the sensing
range can be tailored by varying the ionizable co-monomer and its
concentration. For example, to increase the sensitivity in the
alkaline pH, the hydrogel network can be co-polymerized with
2-(dimethylamino) ethyl methacrylate (pK.sub.a=8.4).
[0072] A key challenge of the pH-sensitive fiber probes for the
real-time measurements in biological applications is the swelling
and shrinkage kinetics. The response time of the fiber probe can
depend on the concentration of the ionizable monomer (AA) and the
ionic strength of the examined solution, where the response time is
directly proportional to the ionizable monomer and inversely
proportional to the buffer concentration. The fiber optic probe
disclosed herein showed a rapid response as it reached the
equilibrium within 60.+-.10 s when the pH was changed from 5.5 to
6.0 and the output signal varied up to .about.17.6 .mu.W (FIG.
11I). Additionally, the fiber probe was examined for reusability by
exposing it to consecutive swelling/shrinkage for three cycles and
no hysteresis was observed (FIG. 11J). This behavior was consistent
with the previous studies of polyHEMA-co-AA where the hydrogel
sensor did not present a significant hysteresis in high ionic
strength solution.
[0073] For the implantable biosensor applications, the silica fiber
probe was replaced with a biocompatible fiber as the silica fiber
causes inflammation in the implantation site and increases the risk
of infection. The biocompatible fiber was made of polyethylene
glycol diacrylate, functionalized with the pH-responsive hydrogel,
and was examined for pH sensing in physiological conditions (FIG.
11K). The trend of the output signals against pH was comparable to
the response of the silica fiber optic probe. The response of
biocompatible fiber optic probe was considerable in the pH range of
5.0 to 7.0 and reached a plateau above pH 7.0. The sensitivity of
the probe was .about.10 nW pH.sup.-1 in the pH range of 5.0 to 7.0
which is slightly less than that observed for the silica fiber
optic probe and is likely due to inefficient light guiding of the
biocompatible core bare fiber. This can be overcome by decreasing
the guided light loss which can be achieved by covering the fiber
core with a biocompatible clad having a low refractive index.
[0074] In contrast to fiber optic probes based on interferometric
techniques, the developed fiber optic probes comprising hydrogel
sensors imprinted with asymmetric microlens arrays do not require
high quality films, coherent light sources, and complex and bulky
readout setups. As compared to the SPR probes that require
multistage and complicated fabrication processes, complex output
signal processing, and costly instrumentation setups to obtain
readouts, the asymmetric microlens array fiber optic probes
disclosed herein can be fabricated via a simple single-stage
process. In addition, the fiber optic probes disclosed herein are
low-cost and portable. Unlike fluorescent probes, the measurement
of the optical power is not prone to photobleaching and the
corresponding shortcomings thereof. Additionally, the asymmetric
microlens array increases the sensor's active area which enhances
the diffusion rate of the analyte into the responsive-hydrogel,
shortening sensor response time. The developed fiber optic probes
can be functionalized with any of a wide array of
stimuli-responsive hydrogels to sense glucose, proteins, nucleic
acids, etc. and can also be utilized in drug delivery
applications.
[0075] According to one or more embodiments, fiber optic probes are
thus provided for remote sensing and implantable biosensing
applications involving alcohol and varying pH levels. As described
above, alcohol- and pH-responsive hydrogels were imprinted with
asymmetric microlens arrays during a UV-curing process and were
attached to the ends of optical fibers. Firstly, the alcohol and pH
hydrogel sensors constrained on glass slides were interrogated in
the transmission and reflection configurations. An optical power
meter and a smartphone were employed for recording the output
signals, which showed an analogous trend confirming the reliability
of using the smartphones to simplify the readout methodology.
Secondly, the fiber optic probes based on alcohol- and
pH-responsive hydrogels showed similar responses to their hydrogel
sensor counterparts constrained on glass slides irrespective of
whether they were utilized in transmission mode or reflection mode.
In addition, the biocompatible fiber optic probe showed an
analogous response to the silica fiber probe; however, the
biocompatible fiber showed less sensitivity, presumably due to
light loss. The fiber optic probes, and related methods, bypass
numerous steps involved in typical fabrication processes of
conventional fiber optic probes based on hydrogels and offers
economical cost and portable readout strategies for reducing
operating costs of fiber optic probes. The developed sensors have
demonstrable and/or promising applications in biological sensing,
point-of-care diagnostics, as well as critical care devices for
real-time measurements.
[0076] Continuous glucose monitoring can enable strict control of
blood glucose concentration in diabetic and intensive care
patients. Optical fibers have emerged as an attractive platform;
however, their practical applications are hindered due to lack of
biocompatible fiber materials, complex and impractical readout
approaches, slow response times, and time-consuming fabrication
processes.
[0077] According to one or more embodiments, fiber optic probes
comprising glucose-responsive hydrogels are provided. The fiber
optic probes can be used for continuous and/or intermittent glucose
monitoring under physiological conditions. The quantification of
glucose was demonstrated using smartphone-integrated fiber optic
probes that overcome existing technical limitations. The fiber
optic probes include a glucose-responsive hydrogel that was
imprinted with an asymmetric microlens array, attached to the end
of a multimode silica optical fiber during photopolymerization, and
used as a sensor for glucose sensing under physiological
conditions. A smartphone and an optical power meter were employed
to record the output signals. The fiber optic probes showed high
sensitivity (2.6 .mu.W mM.sup.-1), rapid response times, and high
glucose selectivity in the physiological glucose range. In
addition, the fiber optic probes attained glucose complexation
equilibrium within 15 min. The lactate interference was also
examined and found to be minimal, .about.0.1% in the physiological
range. A biocompatible hydrogel made of polyethylene glycol
diacrylate was utilized to fabricate a flexible biocompatible
hydrogel fiber to replace the silica fiber, and the end of the
biocompatible hydrogel fiber was functionalized with the
glucose-sensitive hydrogel during the ultraviolet light curing
process. The biocompatible optical fiber was quickly fabricated by
the molding, the readout approach was facile and practical, and the
response to glucose was comparable to the functionalized silica
fiber. The fabricated optical fiber sensors may have applications
in wearable and implantable point-of-care and intensive-care
continuous monitoring systems.
[0078] The fiber optic probes included a glucose recognition agent.
The glucose recognition agent (3-(acrylamido)-phenylboronic acid)
was crosslinked with acrylamide to create glucose-responsive
hydrogel and an asymmetric microlens array (light diffusing
microstructures) was imprinted on the hydrogel. The
glucose-responsive hydrogel was chemically attached to the tip of a
silica multimode fiber during the photopolymerization process. The
functionalized fiber was interrogated for glucose quantification in
transmission mode and reflection mode. Upon glucose complexation
with the boronic acid groups immobilized in the hydrogel matrix,
the hydrogel attached to the optical fiber shifted volumetrically,
altering the curvatures of the imprinted asymmetric microlens
array. The transmitted and the reflected optical powers of the
functionalized fiber were measured by an optical power meter and a
smartphone. In addition, the hydrogel sensor was attached to the
end of a biocompatible hydrogel fiber. The biocompatible
functionalized fiber was flexible and offered the convenience to be
potentially implemented or implanted in biological tissues. The
glucose-responsive fiber optic probe disclosed herein has
additional advantages over the previously developed fiber optic
probes, such as an easy readout process due to its compatibility
with smartphones and the ability to provide readouts without output
signal processing, rapid response times (e.g., about 30 s), short
equilibrium times (e.g., about 15 min), and low-cost,
glucose-selective, plug-and-play technology.
[0079] In some embodiments, the glucose-responsive hydrogel was
fabricated, functionalized with 3-APBA, and stamped with asymmetric
microlens arrays during photopolymerization (FIG. 12A).
Distribution of the asymmetric microlens array and the optical
microscope image are displayed in FIGS. 17A-17B. The stamped
hydrogel sensor was attached to a commercial multimode silica fiber
and an in-house made biocompatible fiber during the polymerization
process (FIGS. 12B-12C). Fabrication of the biocompatible fibers is
shown in FIG. 12D. The immobilized 3-APBA in the hydrogel matrix of
the sensor had a high affinity to glucose molecules forming anionic
boronate due to 1:1 complexation in the hydrogel network,
increasing the osmotic Donnan pressure and causing a corresponding
volumetric shift (FIG. 18). The volumetric shift of the hydrogel
modified the curvature of the asymmetric microlens array stamped on
the hydrogel's surface leading to a change in the focal length of
the microlenses and thus the maximum transmitted/reflected power
that was correlated to the measured glucose concentration.
[0080] The glucose-responsive hydrogel sensor constrained on a
glass substrate and stamped with an asymmetric microlens array was
examined in various glucose concentrations (0 to 50 mM). The sensor
was equilibrated in PBS solution (pH 7.4, ionic strength 150 mM,
24.degree. C.) for 2 h before testing. A stock glucose solution
(100 mM) was prepared in PBS buffer of pH 7.4 and diluted using the
PBS solution to prepare the required glucose concentrations. The
sensor was submerged in glucose-free PBS buffer solution (1 ml) and
illuminated with a green laser (532 nm) and the spatial profile of
the transmitted power (SP.sub.t) was recorded as a reference (FIG.
13A). The glucose-free PBS buffer was replaced with a buffered
glucose solution (1 ml, 5 mM), and the SP.sub.t was recorded after
15 min. The low glucose concentration (5 mM) was replaced with a
higher concentration (10 mM) and the reading was recorded after 15
min, and this protocol was repeated until reaching 50 mM. The
recorded SP.sub.t for the sensor in various glucose concentrations
exhibited Gaussian-shaped profiles and the forward scattering
angles decreased with increasing glucose concentrations. The
diffused light formed a spot having a smaller diameter on the
screen, increasing the maximum optical transmitted power (P.sub.t)
with glucose concentration (FIG. 13B). The P.sub.t readings as a
practical readout method were utilized to monitor the glucose
concentrations. The sensor's response saturated with increasing
glucose concentration; however, it exhibited a linear response
within the range of 0-20 mM, which had a correlation coefficient,
R.sup.2 of 0.99 (FIG. 13C). The P.sub.t increased from 79.4 to 86.7
.mu.W when the glucose concentration increased from 0 to 10 mM, and
reached 99 .mu.W when the glucose concentration increased to 50 mM.
To confirm the working principle, the surface morphology of the
hydrogel sensor was investigated under the optical microscope while
the sensor was submerged in glucose-free PBS buffer and PBS buffer
of 50 mM glucose concentration. Upon glucose-boron complexation,
the sensor swelled in z-direction only as it was constrained on the
glass slide. The surface profile analysis showed that the depth of
the microlens array was higher under glucose-free condition as
compared to the surface's depth in glucose condition. Again, the
hydrogel sensor was examined for glucose sensing, but in this test,
the sensor was illuminated by a broadband white light beam and the
output signals, the maxima transmitted illuminance (L.sub.t), were
measured by a smartphone (FIG. 13D). Thirdly, the sensor was
interrogated in the reflection configuration as the sensor was
illuminated by a monochromatic light (532 nm) at an incident angle
of 45.degree. and the maximum reflected powers (P.sub.r) of the
diffused beam were collected using an optical power meter (FIG.
13D). The ambient light sensor of a smartphone was utilized to
record the output signals to demonstrate the compatibility and the
simplicity of the readout process. The readout for the glucose-free
buffer was 60 lux and jumped up to 69 upon increasing glucose
concentrating from 0 to 20 mM and reached to 75 lux at 50 mM (FIG.
13E). The relationship of the glucose concentration against the
sensor's output signal was consistent with the experiment carried
out using the monochromatic light and the optical power meter (FIG.
13C). The sensor's response was linear for glucose concentration in
the range of 0-20 mM with a correlation coefficient, R.sup.2 of
0.99 and saturated at high glucose concentrations. The hydrogel
sensor consistently detected glucose concentrations whether it was
illuminated by a monochromatic light or a broadband white light and
this is due to the ability of the microlenses array to control the
beam shape of the monochromatic and white light. In reflection
configuration, the P.sub.r increased with glucose concentration
because of the positive volumetric shift of the hydrogel sensor,
decreasing the curvature of the microlenses and consequently the
light diffusion efficiency of the sensor (FIG. 13F). The sensor
behavior was consistent with the experiments that were carried out
in the transmission mode (FIG. 13C). The P.sub.t increased from 2.6
.mu.W to 3.33 .mu.W upon increasing glucose concentration to 20 mM
and reached 3.88 .mu.W at 50 mM (FIG. 13F). The sensor's output
signals saturated at a high glucose concentration (30 mM) and the
correlation coefficient had a linear relationship (R.sup.2=0.99)
for glucose concentration within the range 0-20 mM.
[0081] For in vivo or remote glucose sensing applications, the
hydrogel sensor was attached to an end of a multimode silica fiber
having a diameter of 500 .mu.m. The silica fiber with the hydrogel
sensor attached thereto was utilized for glucose detection in vitro
in both transmission and reflection configurations. In transmission
mode, the fiber optic probe was coupled to a monochromatic light
source (532 nm) and the output signals (P.sub.t) were recorded by
either an optical power meter or a smartphone (FIG. 14A). Optical
microscopy images of the fiber optic probe's cross-section and
photos of the fiber optic probe illuminated by different
monochromatic light sources (FIGS. 14B-14D). The fabrication
process of the silica fiber optic probe included preparing the
hydrogel matrix, functionalizing the hydrogel with 3-APBA,
imprinting the functionalized hydrogel with the asymmetric
microlens array, and attaching the hydrogel sensor to the end of an
optical fiber. These steps were performed in a single step in about
5 min (FIG. 12B). This facile and rapid fabrication approach is one
of the great advantages of the developed hydrogel sensor in
comparison to other fiber optic probes such as fluorescent- and
SPR-based probes. For instance, the preparation of the fluorescent
glucose sensor requires multiple reaction stages and time-consuming
synthesis and purification steps. Similarly, the fabrication of the
SPR fiber probes is complicated and requires many steps, such as
pretreatment of the optical fiber, decladding, depositing a thin
metal layer, immobilizing the glucose sensitive layer, etc.
[0082] The fiber optic probe was tested in glucose concentrations
ranging from 0-50 mM and the P.sub.t for each concentration over
time was recorded at 24.degree. C. (FIG. 14E). When the glucose
concentration was increased, the fiber optic probe's output signal
(P.sub.t) increased, showing a linear trend with a correlation
coefficient R.sup.2 of 0.99 for glucose concentrations in the range
of 5-20 mM. Upon increasing the glucose concentration from 0 to 20
mM, the P.sub.t surged 48 .mu.W, from 602 to 650 .mu.W (FIG. 14F).
For high glucose concentrations ranging from 20 to 50 mM, the
P.sub.t increased 30 .mu.W, indicating declined sensitivity. An
8.3% change was observed when the glucose concentration was
increased from 0 to 20 mM as compared to the 7% change over glucose
concentrations ranging from 0-100 mM for conventional fiber probes.
The fiber optic probe was coupled to a green laser and
re-interrogated for glucose sensing, except a smartphone was
employed to measure the output signals. The maximum transmitted
illuminance (L.sub.t) increased by 69 Lux, from 929 to 998 Lux with
increasing glucose concentrations ranging from 0 to 20 mM; however,
the growth of the output signal was 49 Lux when the glucose
concentration increased from 20 to 50 mM (FIG. 14G). The trend of
the recorded L.sub.t against the glucose concentrations was
comparable to results recorded by the optical power meter. The
fiber optic probe's response was linear for glucose concentrations
in the range of 5-20 mM with a correlation coefficient R.sup.2 of
0.99 and the sensitivity declined at high concentrations as the
sensor saturated. To test the feasibility of utilizing the
broadband white light for sensing as it is safer than lasers for
human body implantation sensing, the fiber optic probe was coupled
to a broadband white light source and re-examined for glucose
concentrations in the range of 0-50 mM and the readout was
collected by a smartphone and an optical power meter (FIG.
14H-14I). The trends of the output signals from the fiber optic
probe immersed in various glucose concentrations were comparable,
irrespective of whether the output signals were recorded by the
smartphone or the optical power meter. The fiber optic probe's
response decreased at high concentrations. Below 30 mM, the
response was linear with a correlation sensor's saturation at high
glucose concentrations might be attributed to the limited
availability of boronate binding sites and the reduced elasticity
of the hydrogel matrix that competed with the volumetric swelling
process. The fiber optic probe interrogation results were similar
to those from previous experiments in which the hydrogel glucose
sensor was constrained on a glass substrate. The fiber sensitivity
was 2.6 .mu.W mM.sup.-1 in the most significant glucose
concentration range (5-20 mM), calculated using the slope of the
linear fit. The output signal of the fiber optic probe shifted by a
coefficient R.sup.2 of 0.99. Advantageously, the probe's response
to glucose concentrations was similar when the coupled light source
was a broadband white light or a monochromatic light source, and
the smartphone was successfully employed for readouts and showed a
reliable response. The readout methodology was simple and low cost
whether the output signal was recorded by a power meter or a
smartphone. This is an advantage of the fiber optic probes
disclosed herein in comparison to other conventional glucose
probes. For instance, interferometric, fluorescent, and SPR fiber
probes require processing of the output signal and high-cost
instruments such as spectrophotometers and fluorometers for
readout.
[0083] The silica fiber optic probe was also tested for glucose
sensing within the concentration range of 0-50 mM in a reflection
configuration, which is the desired mode for in vivo glucose
sensing. In the reflection configuration, a three-terminal coupler
2.times.1 was utilized to connect the fiber optic probe with the
white light source and the optical power meter (FIG. 15A). The
fiber optic probe was submerged in the glucose solution (1 ml) and
the optical reflected power (P.sub.r) was recorded by the optical
power meter. Upon swelling of the hydrogel sensor attached to the
end of the optical fiber, the P.sub.r guided in the optical fiber
increased (FIG. 15B). In reflection mode, the behavior of the
output signal in response to changes in glucose concentrations was
comparable to measurements obtained in transmission mode as the
fiber response was linear within the concentration range of 0 to 20
mM with a correlation coefficient R.sup.2 of 0.99, and the
sensitivity decreased significantly above 20 mM. The optical
reflected power was 318 nW for the glucose-free PBS buffer and
increased to 338 nW at 20 mM concentration with a sensitivity of 1
nW mM.sup.-1 in this glucose range. For the high glucose
concentration range of 20-50 mM, the output signal recorded an
increment of 13 nW.
[0084] The swelling dynamics of the fiber optic probe was studied
at a constant glucose concentration (10 mM) as the P.sub.t was
recorded over time. Upon exposure of the fiber optic probe to the
glucose solution, the binding equilibrium (glucose-boron
complexation) was saturated within 15 min and the response time was
30 s (FIG. 15C). This equilibrium time was one-third of the
response times reported in previous studies, where the saturation
time for the 3-APBA-modified optical fiber was 45 min. For the
diabetic patients, the readout rate required for monitoring glucose
concentration is 0.078 mMmin.sup.-1, and the proposed probe
provided a readout rate of 0.66 mM min.sup.-1, which is 8-fold
higher than the required speed. The stability and reusability of
the silica fiber optic probe were investigated by detecting the
response of the fiber optic probe in four complete and continuous
cycles (FIG. 15D). The probe's response for 10 mM glucose
concentration was monitored for 15 min, followed by a reset using
an acetate buffer (pH 4.6) for .about.10 s, and maintained in PBS
for 15 min buffer before commencing the next cycle. When the probe
was immersed in buffer at pH 4.6, the hydrogel sensor contracted
due to the decrease in the pH below the apparent pK.sub.a value of
the glucose-responsive hydrogel as the charged tetrahedral state of
the 3-APBA transformed to uncharged trigonal planar form releasing
the bound glucose molecules. Upon immersing the functionalized tip
into the PBS buffer of pH 7.4, the attached hydrogel returned to it
is original volume, and consequently the asymmetric microlens array
was reset to its original geometry. These results are significant
as the fiber optic probe exhibited reusability with limited
hysteresis and had comparable sensitivity for each cycle. The
boronic acids bind to cis-diol containing molecules and
.alpha.-hydroxy acids. Fructose and galactose are monosaccharides
present in human blood at low concentrations (<0.1 mM). In
addition, there are many other sugars in blood in the form of
glycoproteins and macromolecular carbohydrates; however, they are
not expected to significantly interfere with the probe's response
as they may not diffuse into the hydrogel matrix and bind to PBA
groups because of their large molecular sizes. Thus, the glucose
selectivity during in vivo sensing was expected to be minimal;
however, lactate is present in blood at a concentration of
0.36-0.75 mM in healthy adults and has a high affinity to bind with
phenylboronic acid by its .alpha.-hydroxy group. Thus, a potential
interference of lactate on the probe's response was interrogated
(FIG. 15E). The lactate solutions were prepared in PBS buffer (pH
7.4) and the probe's response for lactate and glucose were recorded
separately at human body temperature (37.degree. C.) to determine
the potential interference of lactate under the physiological
conditions. The recorded output signals (P.sub.t) of the fiber
optic probe shifted significantly at high lactate concentrations,
but subtly any response was recorded at low lactate concentrations
(1.0 mM). On the contrary, the output signal of the fiber optic
probe considerably shifted at low glucose concentrations within the
physiological range (4.0-8.0 mM) and the probe's response saturated
at higher concentrations. At a lactate concentration of 5.0 mM, the
output signal increased by 1.2% over 15 min as compared to 4%
increase for the same concentration of glucose in the same
interval. Therefore, the interference of the lactate according to
its concentrations in blood would be 0.08%-0.17%. However, the
small molecular weight (Mw: 90 g mol.sup.-1) of lactate molecule
accelerated its diffusion into the hydrogel matrix and its high
affinity to bind with the pendant phenylboronic acid, it has a
limited potential interference in the probe's response.
[0085] The effect of pH on the probe's response was examined as the
probe was submerged in various pH solutions having the same ionic
strength (150 mM) at 24.degree. C. and the P.sub.t was recorded
(FIG. 15F). Increasing the pH induced a positive volumetric shift
leading to an incremental change of the recorded P.sub.t. The
probe's response for glucose detection can depend on the pH of the
solution. The measured P.sub.t increased significantly starting
from pH 6, which was due to swelling of the attached hydrogel
sensor, caused by an increase in the anionic boronate ions in the
hydrogel network. Decreasing the pH below 6 slightly shifted the
output signal, indicating a tenuous growth in the anionic boronate
ions. Furthermore, the effect of temperature on the fiber probe's
response was investigated within the range of 10-45.degree. C.
Raising the solution temperature caused the glucose-responsive
hydrogel to shrink or contract, enhancing the curvature of the
imprinted microlenses, and consequently the output signal
decreased. Within the temperature range of 20-35.degree. C., the
fiber probe's signal slightly shifted, whereas the output signals
changed considerably below 20.degree. C. and above 35.degree. C.
The output signal shifted by 2% when the temperature increased from
10 to 20.degree. C., 0.5% with increases from 20 to 35.degree. C.,
and 3.6% with increases to 45.degree. C. (FIG. 15G). The fiber
optic probe's response to glucose can be calibrated at
physiological conditions to avoid the temperature and pH
interferences.
[0086] Silica fiber optic probes are not compatible with biological
tissues to be implemented for in vivo sensing as they can cause
inflammation at the implanted sites and discomfort to patients.
Therefore, a biocompatible hydrogel fiber was fabricated to replace
the silica fiber. A biocompatible polymer, polyethylene glycol
diacrylate (PEGDA), was utilized to fabricate hydrogel optical
fibers because PEGDA hydrogel counters the adsorption of proteins
such as fibrinogen, albumin, and fibronectin that host the
inflammatory cell interactions. Initially, polymerized PEGDA cubes
of 1 cm side length were prepared at precursor concentrations of
5-90 vol % to determine the optimum concentrations for fabricating
the hydrogel fiber (FIG. 16A). The hydrogel attenuation for
monochromatic light (532 and 650 nm), and broadband white light
were investigated. For monochromatic and white light, increasing
the PEGDA concentration from 5 to 60 vol % considerably reduced the
light attenuation, and above 60 vol % a slight change was detected
(FIGS. 16B-16C). For monochromatic light, the attenuation was 22 dB
cm.sup.-1 at the precursor concentration of 10 vol % and decreased
to .about.1 dB cm.sup.-1 when the precursor concentration reached
50 vol %. The attenuation decreased to .about.0.4 dB cm.sup.-1 with
increasing the precursor concentration to 90 vol %. These results
confirmed that the optical properties of the PEGDA hydrogel
depended on the precursor concentration. The attenuation of the
broadband white light measurements showed higher attenuation for
short wavelengths besides the significant dependence of the
attenuation on the precursor concentration. Considering the
mechanical and optical properties, the hydrogel fiber was made
using a PEGDA precursor concentration of 60 vol %. The end of the
hydrogel optical fiber was functionalized with the
glucose-responsive hydrogel as in the case of the silica fiber. The
hydrogel fiber with a length of 5 cm and a diameter of 950 .mu.m,
was coupled with a broadband white light source and an optical
power meter by the 2.times.1 coupler. The hydrogel fiber optic
probe was interrogated for glucose sensing in reflection mode and
the readings were recorded after 15 min for each glucose
concentration. The output signal increased by 17 nW for glucose
concentrations in the range of 0-20 mM and by 10 nW for glucose
concentration changes from 20-50 mM, presenting an analogous
response to the silica fiber optic probe discussed above (FIG.
16D). The trend of the output signal was linear for the glucose
concentration range of 0 to 20 mM and above this concentration the
sensitivity decreased considerably. Notably, the sensitivity of the
hydrogel fiber optic probe was less than the silica fiber optic
probe which might be attributed to the higher light loss in the
hydrogel fiber as compared to the silica fiber, and which can be
improved by cladding the hydrogel fiber with a low-refractive index
material such as calcium alginate.
[0087] Fiber optic probes are thus provided for continuous glucose
monitoring based on hydrogel sensors attached to the ends of silica
optical fibers and biocompatible hydrogel optical fibers. The
hydrogel sensors could be functionalized during the
photopolymerization of the glucose-responsive hydrogel. The
fabrication process of the fiber optic probe involved preparing the
hydrogel, replicating the asymmetry microlens array, incorporating
the 3-(acrylamido)phenylboronic acid, and attaching the hydrogel
sensor to the end of the optical fiber. This process was executed
in 5 min. The facile and rapid fabrication process is an advantage
of the proposed fiber optic probe for glucose sensing. The PEGDA
hydrogel was utilized to fabricate a biocompatible optical fiber
that can potentially minimize the inflammation in the probe
insertion site. The fiber optic probe's readout was simple,
practical, and low cost as it did not require data processing or
costly equipment. The output signals were recorded by either a
smartphone or an optical power meter, utilizing broadband white
light or monochromatic light sources for illuminating the probe.
Glucose quantification tests were attained in both transmission and
reflection configurations, and effect of pH and temperature on the
probe's response was also examined. The silica fiber optic probe
was highly sensitive and selective for glucose over lactate within
the physiological range as the interference of lactate was trivial
(.about.0.1%). The developed probe presented significant optical,
mechanical, and practical advantages than their previous
counterparts in terms of ease fabrication process, rapid response,
and practical readouts. The fiber optic probes thus can be used for
applications involving in vivo glucose monitoring systems at
point-of-care and intensive care units. To realize broader
applications, the proposed fiber probe can be functionalized with
chelating agents and aptamers for continuously sensing a wide range
of biomolecules such as proteins, DNA, and RNA in clinical
samples.
Discussion of Possible Embodiments
[0088] According to one aspect, a fiber optic probe can include an
optical fiber, and a sensor component attached to the optical
fiber, the sensor component including light diffusing
microstructures (asymmetric microlens array) imprinted on a
stimuli-responsive hydrogel.
[0089] The fiber optic probe of the preceding paragraph can
optionally include, additionally, and/or alternatively, any one or
more of the following features, configurations, and/or additional
components.
[0090] In some aspects, the optical fiber is a biocompatible
hydrogel fiber.
[0091] In some aspects, the asymmetric microlens array includes one
or more microlenses, each of the one or more microlenses
independently having a convex aspherical surface, a plano-convex
aspherical surface, a convex-concave aspherical surface, a convex
spherical surface, a plano-convex spherical surface, or a
convex-concave spherical surface.
[0092] In some aspects, the asymmetric microlens array has at least
one of the following characteristics: microlenses which are
non-uniformly spaced apart; microlenses which are arranged in a
non-periodic configuration; microlenses which are arranged in a
non-ordered configuration; at least two microlenses having
different surface topologies; at least two microlenses having
different base geometries; and at least two microlenses having
different heights.
[0093] In some aspects, the sensor component includes a
glucose-responsive hydrogel.
[0094] In some aspects, the glucose-responsive hydrogel sensor
includes acrylamide; N,N'-methylenebisacrylamide;
3-(acrylamido)-phenylboronic acid (3-APBA); and
2,2-dimethoxy-2-2phenylacetophenone (DMPA).
[0095] In some aspects, the sensor component includes an
alcohol-responsive hydrogel.
[0096] In some aspects, the alcohol-responsive hydrogel sensor
includes 2-hydroxyethylmethacrylate (HEMA); ethylene glycol
dimethacrylate (EGDMA); and 2,2-dimethoxy-2-phenylacetophenone
(DMPA).
[0097] In some aspects, the sensor component includes a
pH-responsive hydrogel.
[0098] In some aspects the pH-responsive hydrogel sensor includes
2-hydroxyethylmethacrylate (HEMA); ethylene glycol dimethacrylate
(EGDMA); acrylic acid (AA); and 2,2-dimethoxy-2-phenylacetophenone
(DMPA).
[0099] According to a further aspect, a method of fabricating a
fiber optic probe can include (a) depositing a light-curable
stimuli-responsive hydrogel precursor solution on a substrate mold
having a surface including an inverse asymmetric microlens array;
(b) contacting an end portion of an optical fiber with the
light-curable stimuli-responsive hydrogel precursor solution
deposited on the substrate mold; and (c) exposing the end portion
of the optical fiber and light-curable stimuli-responsive hydrogel
precursor solution to light to form a stimuli-responsive hydrogel
sensor imprinted with an asymmetric microlens array and attached to
the end portion of the optical fiber.
[0100] The method of fabricating a fiber optic probe of the
preceding paragraph can optionally include, additionally, and/or
alternatively, any one or more of the following features,
configurations, and/or additional components.
[0101] In some aspects, the light-curable stimuli-responsive
hydrogel is synthesized, imprinted with the asymmetric microlens
array, and attached to the end portion of the optical fiber in step
(c).
[0102] In some aspects, the light-curable stimuli-responsive
hydrogel precursor solution includes at least the following: a
monomer, a crosslinking agent, and a photoinitiator.
[0103] In some aspects, the substrate mold is fabricated by
depositing a light-curable prepolymer solution on a master light
diffuser having a surface including a master asymmetric microlens
array; exposing the deposited light-curable prepolymer solution to
light to cure the prepolymer; and releasing the cured prepolymer
from the master light diffuser to obtain the substrate mold, the
substrate mold including the inverse asymmetric microlens
array.
[0104] In some aspects, the optical fiber is fabricated by:
injecting a light-curable monomer solution into a tubular body;
exposing the monomer solution to light to initiate polymerization;
and extracting a polymerized fiber from the tubular body to obtain
the optical fiber.
[0105] In some aspects, the asymmetric microlens array includes one
or more microlenses, each of the one or more microlenses
independently having a convex aspherical surface, a plano-convex
aspherical surface, a convex-concave aspherical surface, a convex
spherical surface, a plano-convex spherical surface, or a
convex-concave spherical surface.
[0106] According to another aspect, a system can include a fiber
optic probe including an optical fiber and a sensor component
attached to the optical fiber, the sensor component including an
asymmetric microlens array imprinted on a stimuli-responsive
hydrogel; a light source coupled to the fiber optic probe, wherein
the light source is configured to transmit light through the
optical sensor; and a light sensor for detecting light transmitted
through the asymmetric microlens array or light reflected from the
asymmetric microlens array.
[0107] The system of the preceding paragraph can optionally
include, additionally, and/or alternatively, any one or more of the
following features, configurations, and/or additional
components.
[0108] In some aspects, the light sensor is a smartphone used to
detect light transmitted through the asymmetric microlens
array.
[0109] In some aspects, the light sensor is an optical power meter
used to detect light reflected from the asymmetric microlens
array.
[0110] In some aspects, the asymmetric microlens array has at least
one of the following characteristics: microlenses having at least
one of the following surfaces: a convex aspherical surface, a
plano-convex aspherical surface, a convex-concave aspherical
surface, a convex spherical surface, a plano-convex spherical
surface, and a convex-concave spherical surface; microlenses which
are non-uniformly spaced apart; microlenses which are arranged in a
non-periodic configuration; microlenses which are arranged in a
non-ordered configuration; at least two microlenses having
different surface topologies; at least two microlenses having
different base geometries; and at least two microlenses having
different heights.
[0111] The following Examples are intended to illustrate the above
invention and should not be construed as to narrow its scope. One
skilled in the art will readily recognize that the Examiners
suggest many other ways in which the invention could be practiced.
It should be understood that numerous variations and modifications
may be made while remaining within the scope of the invention.
Example 1
Hydrogel Alcohol Sensor Fabrication
[0112] Ethylene glycol dimethacrylate (EGDMA) (98%), 2-hydroxyethyl
methacrylate (HEMA) (97%), 2,2-dimethoxy-2-phenylacetophenone
(DMPA) (99%), polyethylene glycol diacrylate (PEGDA) (mw: 700 Da),
2-hydroxy-2-methylpropiophenone (2-HMP) (97%), dimethyl sulfoxide
(DMSO) (99.9%), ethanol, propan-2-ol, sodium phosphate monobasic
(NaH.sub.2PO.sub.4), sodium phosphate dibasic (NaH.sub.2PO.sub.4),
and acrylic acid (AA) were purchased from Sigma Aldrich and used
without further purification.
[0113] The precursor consisted of HEMA (92.5 mol %) and EGDMA (7.5
mol %) was mixed with DMPA (2% wt/vol) in propan-2-ol. The monomer
solution (20 .mu.l) was drop cast on the asymmetric microlens
arrays (diffuser surface), covered with a salinized glass piece,
and cured by a UV lamp (365 nm) for 1 h. The polymerized sensor was
washed with DI water/ethanol (1:1, v/v) and preserved at 24.degree.
C.
Example 2
Hydrogel pH Sensor Fabrication
[0114] Ethylene glycol dimethacrylate (EGDMA) (98%), 2-hydroxyethyl
methacrylate (HEMA) (97%), 2,2-dimethoxy-2-phenylacetophenone
(DMPA) (99%), polyethylene glycol diacrylate (PEGDA) (mw: 700 Da),
2-hdroxy-2-methylpropiophenone (2-HMP) (97%), dimethyl sulfoxide
(DMSO) (99.9%), ethanol, propan-2-ol, sodium phosphate monobasic
(NaH.sub.2PO.sub.4), sodium phosphate dibasic (NaH.sub.2PO.sub.4),
and acrylic acid (AA) were purchased from Sigma Aldrich and used
without further purification.
[0115] The precursor consisted of HEMA (91.5 mol %), EGDMA (2.5 mol
%), and acrylic acid (6 mol %), was mixed with DMPA in propan-2-ol
(2%, wt/vol). The monomer solution (20 .mu.l) was pipetted on the
asymmetric microlens arrays, covered with a salinized glass piece,
and cured by the UV lamp (365 nm) for 1 h. The polymerized sensor
was washed with DI water/ethanol (1:1, v/v) and preserved at
24.degree. C.
Example 3
Hydrogel Optical Fiber Fabrication
[0116] PEGDA monomer was mixed with 2-hydroxy-2-methylpropiophenone
(2-HMP) (5 vol %) in DI water. The dilution of PEGDA in DI water
was varied from 5 to 90 vol %. The prepared solution (200 .mu.l)
was injected into a polyvinyl chloride tube having an inner
diameter of 1 mm and the tube was exposed to UV light (365 nm) for
30 min. The optical fiber was extracted from the tube by applying
water pressure using a syringe. The optical fiber was washed with a
mixture of ethanol and DI water (1:1, v/v). The tip of the fiber
was functionalized with the pH-sensitive hydrogel by dipping the
tip in a pH-sensitive solution (10 .mu.l) that was pipetted on the
asymmetric microlens arrays and was exposed to UV light for 1 h. To
create a probe, the tip of the fiber was salinized and dipped in
either alcohol or pH-sensitive solutions during the curing process.
The functionalized tip was washed in DI water/ethanol (1:1, v/v)
and preserved at 24.degree. C.
Example 4
Testing the Hydrogel Sensor Constrained on the Glass Slide
[0117] The stimuli-responsive hydrogel imprinted with microlens
arrays and attached chemically on the glass slide was submerged in
1 ml of the tested solution in a plastic cuvette fixed on a
rotating stage. White light source or laser pointer was fixed on
the same rotating stage to illuminate the senor. S.sub.t, and
P.sub.t were recorded by a photodiode that was fixed and immobile
on the optical bench. Also, the smartphone was fixed to pick up the
maximum transmitted luminance (L.sub.t) exploiting the ambient
light senor of smartphone for sensing measurements.
Example 5
Testing the Fiber Probe in the Transmission Mode
[0118] The fiber probe was coupled with a white light source/laser
pointer at one end and the other end that is functionalized was
soaked in the tested solution container. Below the tested solution
container, the photodiode detector/smartphone was fixed to collect
the P.sub.t/L.sub.t.
Example 6
Testing the Fiber Probe in the Reflection Mode
[0119] The fiber probe was coupled with the seven fibers terminal
of 2.times.1 coupler. The light source was connected with the
coupler terminal of only one fiber and the photodiode was connected
with coupler terminal of six fibers. Therefore, one fiber was
illuminating the sensing probe and the six fiber were collecting
the reflected light in the probe to be guided into the
photodetector.
Example 7
Glucose Monitoring
[0120] Materials. Polyethylene glycol diacrylate (PEGDA) (mw: 700
Da), acrylamide (AM) (98%), 3-(acrylamido)-phenylboronic acid
(3-APBA) (98%), sodium L-lactate, N,N-methylenebisacrylamide (99%),
D-(+) glucose (99.5%), 2,2-dimethoxy-2-phenylacetophenone (DMPA)
(99%), 2-hdroxy-2-methylpropiophenone (2-HMP) (97%), phosphate
buffered saline tablets (PBS), dimethyl sulfoxide (DMSO) (99.9%),
sodium phosphate monobasic (NaH.sub.2PO.sub.4), and sodium
phosphate dibasic (NaH.sub.2PO.sub.4) were purchased from Sigma
Aldrich and used without further purification.
Example 8
Fabrication of the Hydrogel Sensor Constrained on a Glass Slide
[0121] The precursor solution consisted of acrylamide (78.5 mol %),
N, N'-methylenebisacrylamide (1.5 mol %), and 3-APBA (20 mol %) was
mixed with DMPA (2% wt/vol) in DMSO and the monomer dilution was
1:2 wt/vol. The monomer solution (100 .mu.l) was drop-cast on the
asymmetric microlens array surface, and subsequently, was covered
with a salinized glass piece, and was polymerized by UV lamp (365
nm) for 5 min. The polymerized sensor was washed with DI
water/ethanol (1:1 v/v) and preserved in PBS solution at pH
7.4.
Example 9
Functionalization of the Silica and the Hydrogel Fibers
[0122] To functionalize the optical fiber with the glucose
responsive hydrogel, the fiber's tip was silanized and dipped in
the glucose-sensitive solution (10 .mu.l) that was drop-cast on the
asymmetric microlens array surface (AMLA) and was exposed to the UV
light for 5 min. The functionalized fiber was preserved in the PBS
solution at pH 7.4.
Example 10
Fabrication of the Biocompatible Optical Fiber
[0123] PEGDA monomer was mixed with 2-hydroxy-2-methylpropiophenone
(2-HMP) (5 vol %) in DI water. The dilution of PEGDA in DI water
was varied from 5 to 90 vol %. The prepared solution (200 .mu.l)
was injected into a polyvinyl chloride tube with an inner diameter
of 1 mm and the tube was exposed to UV light (365 nm) for 30 min.
The optical fiber was extracted from the tube by applying water
pressure using a syringe. The optical fiber was washed with a
mixture of ethanol and DI water (1:1, v/v).
* * * * *