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Citation: Sabel-Grau, T.; Tyushina,
A.; Babalik, C.; Lensen, M.C. UV-VIS
Curable PEG Hydrogels for
Biomedical Applications with
Multifunctionality. Gels 2022,8, 164.
https://doi.org/10.3390/
gels8030164
Academic Editors: Yang Liu and Kiat
Hwa Chan
Received: 4 February 2022
Accepted: 3 March 2022
Published: 5 March 2022
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gels
Article
UV-VIS Curable PEG Hydrogels for Biomedical Applications
with Multifunctionality
Tina Sabel-Grau * , Arina Tyushina, Cigdem Babalik and Marga C. Lensen *
Nanopatterned Biomaterials (Secr. C 1), Department of Chemistry, Technische Universität Berlin,
Strasse des 17. Juni 115, 10623 Berlin, Germany; [email protected] (A.T.); [email protected] (C.B.)
*Correspondence: T[email protected] (T.S.-G.); [email protected] (M.C.L.)
Abstract:
Multifunctional biomedical materials capable of integrating optical functions are highly
desirable for many applications, such as advanced intra-ocular lens (IOL) implants. Therefore,
poly(ethylene glycol)-diacrylate (PEG-DA) hydrogels are used with different photoinitiators (PI). In
addition to standard UV PI Irgacure, Erythrosin B and Eosin Y are used as PI with high sensitivity in
the optical range of the spectrum. The minimum PI concentrations for producing new hydrogels with
PEG-DA and different PIs were determined. Hydrogel films were obtained, which were applicable
for light-based patterning and, hence, the functionalization of surface and volume. Cytotoxicity tests
confirm cytocompatibility of hydrogels and compositions. Exploiting the correlation of structure and
function allows biomedical materials with multifunctionality.
Keywords:
hydrogels; photopolymers; volume holography; photo curing; multifunctional
biomedical
biomaterials; light-responsive materials
1. Introduction
In tissue engineering and medical science, hydrogels are particularly suitable as tissue
scaffolds due to their tunable properties including water content, swellability, diffusivity
and stiffness [
1
,
2
]. In fact, many applications are opened up by the explicit control over
molecular structure and mechanical properties, such as elasticity, cross-linking degree
or surface morphology [
3
]. Using light to control properties, hydrogels are well-suited
scaffolds for light-responsive functionality [
4
]. Such stimuli-responsive hydrogel materials
can change their mechanical properties upon exposure to light. However, relatively little
has been studied with respect to the their optical properties and little attention has been
paid to their potential photonic functionalities [
5
]. Control over optical properties and the
resulting integration of optical functionality open up new opportunities for multifunctional
biomedical materials such as advanced intraocular lens (IOL) implants.
Cataract, the irreversible turbidity of the natural lens of the eye, is one of the most
common causes for global blindness and can only be treated by replacing the clouded lens
with an artificial IOL implant. Among the state-of-the-art IOLs are modern foldable hy-
drogel lenses [
6
]. Persistent problems with IOLs include postoperative calcification [
7
] and
secondary cataract [
8
]. The processes underlying such postoperative clouding, emerging
in vivo from interaction with the biological environment, are still not well understood.
This is where the idea of volume holographic structuring comes into play. Prospective
IOLs, based on multifunctional biomedical material with integrated optical functionality,
could fulfill their function—i.e., to focus the light onto the retina—with an optically struc-
tured volume [
9
]. As a result, the shape and surface of the IOL remain free and available
for other purposes. Thus, subsequent surface modifications remain optional to achieve
specific interactions with the biological environment. In order to make this possible, we
propose a strategy to combine the optical structuring of the volume and a specific modi-
fication of the surface. Therefore, volume holographic structuring can be applied for the
Gels 2022,8, 164. https://doi.org/10.3390/gels8030164 https://www.mdpi.com/journal/gels
Gels 2022,8, 164 2 of 8
integration of three-dimensional optical structures with specific functionality in terms of
diffractive properties.
Volume holography is a very interesting field of application for photo-responsive
polymers, where diffractive structures are induced by a spatially modulated holographic
exposure [
10
]. Holographic elements such as diffractive structures can accommodate
classical optical functions, while at the same time being extremely flat in shape and low
in weight. This gives rise to a great potential for replacing classical refractive optical
systems or extending them with new functionalities. The prerequisite in each case is
the availability of suitable, photo-patternable materials that can exhibit function through
structure. An example of such diffractive structures with classical optical function includes
holographic lenses.
Poly(ethylene glycol) (PEG)-based hydrogels are generally promising as tissue-engineering
scaffolds due to their biocompatibility and intrinsic resistance to protein adsorption and cell
adhesion [
11
]. Furthermore, poly(ethylene glycol)-diacrylate (PEG-DA) hydrogels can be
used as model materials for the generation of internal 3D patterns [
12
]. Acrylate-terminated
PEG macromers undergo rapid polymerization in the presence of photoinitiators that
generate radicals when exposed to light [
13
]. This makes PEG-DA hydrogels interesting
as scaffolds into which desired bioactivity can be tailored via light-based patterning [
12
].
In this context, it was shown that hydrogels can also be structured photolithographically
using diffusion processes—which are the basis for volume holography.
Additionally, the micropatterning of PEG-based hydrogels with gold nanoparti-
cles allows for the fabrication of functionalized PEG-based hydrogel films [
14
,
15
]. The
integration—and holographic assembly—of nanoparticles in turn enables the modifica-
tion of optical properties on the microscale and nanoscale in the form of holographic
nanoparticle-polymer composite gratings [16].
In all this, the type of photoinitiator (PI) used is key for the specific photo-response
of a certain material. The properties of the PI has strong influence on holographic grating
formation in the respective material [
17
]. It also influences how well certain conditions are
met, such as resistance to humidity [
18
]. Eosin-Y (EY) and Erythrosin B (EB) are amongst the
possible PIs applied for holographic grating formation in an AA/PVA photopolymer [
19
].
EY is used as a PI due to its excellent spectroscopic properties, which makes it suitable for
use with light sources in the visible range and safe for living organisms [
20
]. EB can only
be used for free radical polymerization [19].
2. Results and Discussion
2.1. Gel Formation
PEG-DA was mixed with PI (Irgacure, EB and EY, respectively). Films were prepared
by photopolymerization with 366 nm for 1 h. In terms of optical transparency, mechanical
integrity, flexibility, and stability, the new gels compare well with other gels based on
PEG-DA [2123].
For PEG-DA with Irgacure, EB and EY as PI, a minimum concentration of PI was
needed to make gel. With less PI concentration, no hydrogel was formed. The minimum
concentration for the different PIs is shown in Table 1. We found a minimum PI concen-
tration for producing the new hydrogels with PEG-DA and different PIs to be 0.025% for
Irgacure, 0.1% for EB and 0.5% for EY, respectively.
Table 1. Minimum PI concentration to make gel for the different PIs.
Photoinitiator (PI) Minimum PI Concentration to Make Gel with PEG-DA
Irgacure 2959 0.025%
EB 0.1%
EY 0.5%
Gels 2022,8, 164 3 of 8
2.2. UV-Vis Spectra
Figure 1shows the UV-Vis spectra before and after crosslinking for the novel PIs. In
general, for all new PEG-DA hydrogels, we find spectra shifted somewhat toward higher
wavelengths compared to the pure PIs [
24
,
25
], while crosslinking tends to cause a small
shift toward lower wavelengths, as already substantiated in the literature [26].
Gels 2022, 8, x FOR PEER REVIEW 3 of 8
2.2. UV-Vis Spectra
Figure 1 shows the UV-Vis spectra before and after crosslinking for the novel PIs. In
general, for all new PEG-DA hydrogels, we find spectra shifted somewhat toward higher
wavelengths compared to the pure PIs [24,25], while crosslinking tends to cause a small
shift toward lower wavelengths, as already substantiated in the literature [26].
While Irgacure, which is an often employed and suitable photoinitiator for biomateri-
als research, has an absorption maximum in the UV/Vis-spectrum around 300 nm [24], the
novel dyes under investigation display a strong absorption of visible light with wave-
lengths up to 550 nm (see Figure 1).
Figure 1. UV-Vis spectra for the novel PIs (EB and EY) with PEG-DA before and after crosslinking,
respectively. The hydrogels with new PIs (EB and EY) feature good spectroscopic properties, allow-
ing for use with light sources in the visible range.
With EB as PI, the absorption maximum before crosslinking was around 552 nm with
a shoulder at 514 nm. After crosslinking, the absorption peak can be observed at 550 nm
with a shoulder at 512 nm. The typical color for the hydrogel with EB as PI is pink, as
shown in Figure 1.
With EY as PI, the absorption maximum before crosslinking was around 542 nm with
a shoulder at 507 nm. After crosslinking, the absorption peak can be observed at 543 nm
with a shoulder at 506 nm. The typical color for the hydrogel with EY as PI is orange, as
shown in Figure 1.
The major advantage of the new PIs (EB and EY) over the standard Irgacure is their
high sensitivity in the optical range of the spectrum, which enables optical patterning—
Figure 1.
UV-Vis spectra for the novel PIs (EB and EY) with PEG-DA before and after crosslinking,
respectively. The hydrogels with new PIs (EB and EY) feature good spectroscopic properties, allowing
for use with light sources in the visible range.
While Irgacure, which is an often employed and suitable photoinitiator for biomaterials
research, has an absorption maximum in the UV/Vis-spectrum around 300 nm [
24
], the
novel dyes under investigation display a strong absorption of visible light with wavelengths
up to 550 nm (see Figure 1).
With EB as PI, the absorption maximum before crosslinking was around 552 nm with
a
shoulder at 514 nm. After crosslinking, the absorption peak can be observed at 550 nm
with a shoulder at 512 nm. The typical color for the hydrogel with EB as PI is pink, as
shown in Figure 1.
With EY as PI, the absorption maximum before crosslinking was around 542 nm with
a shoulder at 507 nm. After crosslinking, the absorption peak can be observed at 543 nm
with a shoulder at 506 nm. The typical color for the hydrogel with EY as PI is orange, as
shown in Figure 1.
The major advantage of the new PIs (EB and EY) over the standard Irgacure is their
high sensitivity in the optical range of the spectrum, which enables optical patterning—e.g.,
by volume holography. To counter the disadvantage of strong coloring, the composition
Gels 2022,8, 164 4 of 8
could be optimized, e.g., by use of a crosslinker so that the concentrations of EB and EY can
be reduced, respectively.
In the next step, the respective optical response must be determined depending on the
composition. In some cases (such as with an organic cationic ring-opening polymerization
system), competing effects regarding the contribution to the optical grating formation can
be observed [
27
]. It is also known that optical shrinkage can have significant influence on
grating formation [
28
] and that the amount of PEG in a composition affects film shrinkage,
as well as its optical properties [
29
]. Furthermore, we have also observed that photoini-
tiators may contribute to light-induced modification of optical properties and subsequent
pattern formation as well [30].
2.3. Cytotoxicity Tests
A live/dead staining assay has been used to study the cell viability after incubation
with PI EB and EY and also EB 0.1% with PEG-DA before and after crosslinking for 24 h. In
the live/dead staining assay, dead cells turn up red, while living cells turn up green when
observed with a fluorescence microscope. As shown in Figure 2, all cells but one appear to
be green, indicating that PIs and hydrogel (PEG-DA with 0.1% PI EB) are cytocompatible
and suitable as substrates for studying the behaviour of L929 cells at the biointerface.
Gels 2022, 8, x FOR PEER REVIEW 4 of 8
e.g., by volume holography. To counter the disadvantage of strong coloring, the compo-
sition could be optimized, e.g., by use of a crosslinker so that the concentrations of EB and
EY can be reduced, respectively.
In the next step, the respective optical response must be determined depending on
the composition. In some cases (such as with an organic cationic ring-opening polymeri-
zation system), competing effects regarding the contribution to the optical grating for-
mation can be observed [27]. It is also known that optical shrinkage can have significant
influence on grating formation [28] and that the amount of PEG in a composition affects
film shrinkage, as well as its optical properties [29]. Furthermore, we have also observed
that photoinitiators may contribute to light-induced modification of optical properties
and subsequent pattern formation as well [30].
2.3. Cytotoxicity Tests
A live/dead staining assay has been used to study the cell viability after incubation
with PI EB and EY and also EB 0.1% with PEG-DA before and after crosslinking for 24 h.
In the live/dead staining assay, dead cells turn up red, while living cells turn up green
when observed with a fluorescence microscope. As shown in Figure 2, all cells but one
appear to be green, indicating that PIs and hydrogel (PEG-DA with 0.1% PI EB) are cyto-
compatible and suitable as substrates for studying the behaviour of L929 cells at the bio-
interface.
Figure 2 shows fluorescent images of cell tests by live/dead cell assay after being in-
cubated for 24 h with cell line L929. Cell tests shown in Figure 2 confirm cytocompatibility
of PEG-DA hydrogels and PIs, hence affirming its aptitude for biomedical applications.
Figure 2. Fluorescent images of cells test by live/dead cell assay with L929 after incubated for 24 h.
(a) Control cells; (b) EB; (c) EY; (d) EB 0.1% with PEG-DA; (e) optical micrograph of cross-linked
EB/PEG-DA hydrogel; (f) fluorescence image of cross-linked EB/PEG-DA hydrogel. Scale bar de-
picts 50 µm.
3. Conclusions
In addition to the standard photoinitiator Irgacure, Erythrosin B (EB) and Eosin Y
(EY) were used as photoinitiators (PI) in PEG-DA hydrogel. We have determined the min-
imum PI concentration for producing new hydrogels with PEG-DA for the different PIs
respectively. All the PIs are cytocompatible and suitable as substrates for studying the
behaviour of L929 cells at the biointerface.
Figure 2.
Fluorescent images of cells test by live/dead cell assay with L929 after incubated for 24 h.
(
a
) Control cells; (
b
) EB; (
c
) EY; (
d
) EB 0.1% with PEG-DA; (
e
) optical micrograph of cross-linked
EB/PEG-DA hydrogel; (
f
) fluorescence image of cross-linked EB/PEG-DA hydrogel. Scale bar depicts
50 µm.
Figure 2shows fluorescent images of cell tests by live/dead cell assay after being
incubated for 24 h with cell line L929. Cell tests shown in Figure 2confirm cytocompatibility
of PEG-DA hydrogels and PIs, hence affirming its aptitude for biomedical applications.
3. Conclusions
In addition to the standard photoinitiator Irgacure, Erythrosin B (EB) and Eosin Y
(EY) were used as photoinitiators (PI) in PEG-DA hydrogel. We have determined the
minimum PI concentration for producing new hydrogels with PEG-DA for the different
PIs respectively. All the PIs are cytocompatible and suitable as substrates for studying the
behaviour of L929 cells at the biointerface.
The new PIs (EB and EY) feature good spectroscopic properties, allowing for their
application with light sources in the visible range and, thus, for applications in volume
Gels 2022,8, 164 5 of 8
holography. Cytotoxicity test with cell line L929 were performed to confirm cytocompati-
bility of hydrogels and PIs. This opens up many options for PEG-DA hydrogels with PIs as
multifunctional biomedical applications.
The strategy to combine optical structuring of the volume and specific modification
of the surface is particularly interesting for the design of advanced intraocular lens (IOL)
implants: based on a multifunctional biomedical material with integrated optical func-
tionality and operating by the principle ‘function by structure’, such a new type of IOL
is expected to attain enhanced functionality [
9
]. The optical functionality of an IOL with
integrated holographic lens as a diffractive element consists in focusing the light onto the
retina. Several holographic elements can be combined in stacks, where the functionality of
the individual elements overlap. The selectivity of a stack then results in a superposition of
Bragg selectivity of the individual elements [31].
Beyond an enhanced functionality, the transfer of the optical functionality from the
surface into the volume of the IOL implant brings further benefits such as the free interface
for specific interaction with the biological environment. As the existing problems with
conventional IOLs, such as postoperative clouding, emerge
in vivo
from interactions with
the biological environment, they could be better addressed with free-surface IOLs.
The next step towards such a multifunctional optical material is to better understand
the processes that underlay optical structuring, such as the interplay of polymerization
and diffusion in the case of holographic gratings. Here, the general approach is to un-
derstand holographic grating formation as a consequence of photopolymerization and
mass transport processes: local polymerization is induced by a light pattern projected
into the photosensitive medium. Polymerization proportional to the light intensity results
in the induction of a chemical gradient, followed by monomer diffusion and subsequent
polymerization. The final grating is formed as a periodic modulation of optical properties,
according to the recording light pattern [10].
It now remains to be clarified what role the individual components play in the forma-
tion of optical structures in cases of PEG-DA hydrogels with EB and EY. Furthermore, it
remains to be examined if other additives—such as crosslinker or dopant, e.g., in the form
of azobenzene-functionalized acrylates or gold nanoparticles—have a positive effect on the
formation of optical patterns.
4. Materials and Methods
4.1. Preparation of PEG Hydrogels
4.1.1. Chemicals
Poly(ethylene glycol) diacrylate (PEG, Mn 575) and 2-hydroxy-4
0
-(2-hydroxyethoxy)-2-
methylpropiophenone (photoinitiator (PI)—Irgacure 2959), Erythrosin B and Eosin Y were
from Sigma-Aldrich Chemie GmbH (Steinheim, Germany). The chemical structures of the
hydrogel components are shown in Figure 3.
4.1.2. Synthesis of PEG Based Photopolymer with PIs
PEG-DA was used as precursor. It was mixed with PI (Irgacure, EB and EY, respec-
tively). PI concentration varied between 1% and 6 ppm. The chemical structures of different
PIs are shown in Figure 3. For the good mixing of both substances, the mixture was soni-
cated for around 30 min. At first, the mixture was converted in a cuvette and measured
with a UV-Vis spectrometer to obtain spectra before crosslinking. Then, the mixture was
dispensed on a glass slide and covered with a thin glass cover slip to achieve a flat and thin
hydrogel sample. The glass-sandwich was placed under a UV-light source (366 nm) for
60 min and the glass cover slip was peeled off. A flat, thin standalone hydrogel film was
received and also prepared for UV-Vis measurement. Therefore, the hydrogel was placed
on a thin glass cover slip and measured with a UV-Vis spectrometer to obtain spectra after
crosslinking.
Gels 2022,8, 164 6 of 8
Gels 2022, 8, x FOR PEER REVIEW 6 of 8
Figure 3. Irgacure 2959, Erythrosin B and Eosin Y are used as photoinitiators (PI); PEG-DA as a
precursor for PEG hydrogel.
4.1.2. Synthesis of PEG Based Photopolymer with PIs
PEG-DA was used as precursor. It was mixed with PI (Irgacure, EB and EY, respec-
tively). PI concentration varied between 1% and 6 ppm. The chemical structures of differ-
ent PIs are shown in Figure 3. For the good mixing of both substances, the mixture was
sonicated for around 30 min. At first, the mixture was converted in a cuvette and meas-
ured with a UV-Vis spectrometer to obtain spectra before crosslinking. Then, the mixture
was dispensed on a glass slide and covered with a thin glass cover slip to achieve a flat
and thin hydrogel sample. The glass-sandwich was placed under a UV-light source (366
nm) for 60 min and the glass cover slip was peeled off. A flat, thin standalone hydrogel
film was received and also prepared for UV-Vis measurement. Therefore, the hydrogel
was placed on a thin glass cover slip and measured with a UV-Vis spectrometer to obtain
spectra after crosslinking.
4.2. Cell Culture
4.2.1. Chemicals
Mouse fibroblast L929 cells were provided by Dr. Lehmann, Fraunhofer Institute for
Cell Therapy and Immunology, IZI, Leipzig, Germany. RPMI 1640 medium, Trypsin, Fe-
tal Bovine Serum (FBS) and Penicillin/Streptomycin (PS) were provided by PAA Labora-
tories GmbH, Austria, and cell culture plates are from SPL Live Sciences Inc., Seoul, Korea.
The Incubator CB150 Series was from Binder GmbH, Germany. Phosphate Buffered Saline
solution (Dulbecco’s PBS) was purchased from Sigma-Aldrich Chemie, GmbH, Germany.
The counter chamber was from Marienfeld Superior (Paul Marienfeld GmbH & Co., KG,
Lauda-Königshofen, Germany).
4.2.2. Cell Culture Experiments
The mouse fibroblasts L929 cells were cultured in the tissue culture plate in RPMI
1640 medium with the addition of 10% Fetal Bovine Serum (FBS) and 1% Penicillin/Strep-
tomycin (PS) in a cell culture plate in an incubator at controlled temperature (37 °C) and
CO2 atmosphere (5%). The cells were grown in a cell culture plate and cell culture exper-
iments were performed when a confluency of 75% to 95% was reached.
Figure 3.
Irgacure 2959, Erythrosin B and Eosin Y are used as photoinitiators (PI); PEG-DA as a
precursor for PEG hydrogel.
4.2. Cell Culture
4.2.1. Chemicals
Mouse fibroblast L929 cells were provided by Dr. Lehmann, Fraunhofer Institute for
Cell Therapy and Immunology, IZI, Leipzig, Germany. RPMI 1640 medium, Trypsin, Fetal
Bovine Serum (FBS) and Penicillin/Streptomycin (PS) were provided by PAA Laboratories
GmbH, Austria, and cell culture plates are from SPL Live Sciences Inc., Seoul, Korea. The
Incubator CB150 Series was from Binder GmbH, Germany. Phosphate Buffered Saline
solution (Dulbecco’s PBS) was purchased from Sigma-Aldrich Chemie, GmbH, Germany.
The counter chamber was from Marienfeld Superior (Paul Marienfeld GmbH & Co., KG,
Lauda-Königshofen, Germany).
4.2.2. Cell Culture Experiments
The mouse fibroblasts L929 cells were cultured in the tissue culture plate in RPMI
1640 medium with the addition of 10% Fetal Bovine Serum (FBS) and 1% Penicillin/Streptomycin
(PS) in a cell culture plate in an incubator at controlled temperature (37
C) and CO
2
atmo-
sphere (5%). The cells were grown in a cell culture plate and cell culture experiments were
performed when a confluency of 75% to 95% was reached.
The hydrogel samples were prior washed with water and kept in a PBS solution for
around 30 min before cell culture experiments. As soon as a confluency of at least 75%
was reached, the cells were washed with PBS, detached by using trypsin and, after the
centrifugation process, a new medium was added on the cells and mixed properly. An
amount of 10
µ
L of this cell medium solution was placed on a cell counter chamber in order
to count the cell number by using an optical microscope and to achieve a concentration
of 40,000 cells/mL. Depending on the counted cell number, the cell solution was mixed
with a defined amount of new medium. The samples were placed in a TCPS plate or on the
washed and precut hydrogel. The samples were then cultured within these cells for 24 h, at
37 C in a 5% CO2atmosphere in a TCPS.
4.2.3. Live Dead Cytotoxicity Assay
The live dead cytotoxicity assay is a fluorescence-based method for checking the
viability of cells. Hereby, the cells are stained with fluoresceindiacetete (FBS) and pro-
pidiumiodid (PI) molecules. FBS is dissociated in the cytoplasma of live cells into green
fluorescence molecules and, due to the size and charge of the PI molecules, they only can
Gels 2022,8, 164 7 of 8
enter into the cell cytoplasm when the cell membranes are damaged and are bound to
nucleic acids, which appear then as red fluorescence color. In this manner, the live cells
appear as green-stained cells and dead cells appear as red-stained cells in a fluorescent
microscope image.
For the live dead assay, a 1:1 v/vsolution of PI and FBS in PBS was prepared and
added into the cell culture solution in a dark environment. Immediately after the mixtures
are prepared, fluorescence images are taken.
4.3. Analytical Instruments
UV-Vis spectra were obtained with Cary 4000 UV-Vis Spectrometer (Agilent Tech-
nologies, Santa Clara, CA, USA). The spectral range from 300 to 900 nm was measured at
room temperature. Liquid samples (before crosslinking) were converted in a cuvette for
measurement. The flat, thin standalone hydrogel films (after crosslinking) were placed on a
thin glass cover slip for measurement with a UV-Vis spectrometer.
The results from cell culture experiments were observed via the optical microscope
from Carl Zeiss, Germany, and analyses were performed with the AxioVision V4.8.2
software (Carl Zeiss, Oberkochen, Germany).
Author Contributions:
Conceptualization, T.S.-G.and M.C.L.; investigation, A.T. and C.B.;
writingoriginal
draft preparation, review and editing, T.S.-G.; supervision, M.C.L.; project administration and funding
acquisition, T.S.-G. All authors have read and agreed to the published version of the manuscript.
Funding:
This research was funded by Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation), grant number SA 2990/1-1. The APC was funded by DFG.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design
of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.
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