Bioinspired adenine-dopamine immobilized polymer hydrogel adhesives for tissue engineering

Article abstract of DOI:10.1039/d0cc04909c

Nontoxic adhesive hydrogels are of great importance in tissue engineering. Herein, we report a simple synthesis of a few biocompatible hydrogels from adenine and dopamine immobilized polyacrylic acid (PAA) and alginic acid (Alg) polymers. The adenine-dopamine adduct incorporated hydrogels showed enhanced adhesiveness, transparency and biocompatibility, and induced cell proliferation in 2D and 3D-cell culture models within 24 h. Moreover, blending the modifiedPAAand Alg polymers (P2P4) further increased the stability and bioactivity of the hydrogel. Such biogels can be developed as smart materials for biomedical applications.

Full text of DOI:10.1039/d0cc04909c

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DOI: 10.1039/D0CC04909C
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Bioinspired Adenine-Dopamine Immobilized Polymer Hydrogel
Adhesives for Tissue Engineering
Received 00th January 20xx,
Accepted 00th January 20xx
Saurabh Joshi,a,b Gomathi Mahadevan, Sandeep Verma,* Suresh Valiyaveettil*
a
b
a
DOI: 10.1039/x0xx00000x
Nontoxic adhesive hydrogels are of great importance in tissue materials.14 The nucleobases, especially adenine and
engineering. Herein, we report a simple synthesis of a few dopamine incorporated polymeric hydrogels are not yet tested
1
5
biocompatible hydrogels from adenine and dopamine immobilized for cell adhesion or cell signaling.
polyacrylic acid (PAA) and alginic acid (Alg) polymers. The adenine Polyacrylic acid (PAA) and alginic acid (Alg) based gels show
dopamine adduct incorporated hydrogels showed enhanced good swelling behaviour, pH sensitivity, and accessible for
-
1
6-
adhesiveness, transparency, biocompatibility and induced cell further chemical modifications to obtain adhesive materials.
proliferation in 2D and 3D-cell culture models within 24 hr.
1
8
Unlike reported hydrogels from adenine or dopamine
Moreover, blending the modified PAA and Alg polymers (P2P4) functionalized polymers, here we prepare an adenine-
further increased the stability and bioactivity of the hydrogel. dopamine adduct and immobilize on the PAA or Alg polymer
Such biogels can be developed as smart materials for biomedical backbone (SI, Scheme S1A). This strategy allowed us to control
applications.
the concentration & distribution of the bioactive molecules
and to include the adenine-dopamine adduct inside a three-
dimensional gel. The properties of such hydrogels are
compared with the gels prepared from adenine functionalized
PAA or Alg polymer. Our design strategy, synthetic scheme and
the characterization details of the polymers are given in the
supporting information (Figure S1-S9).
Hydrogels are interesting materials owing to their
functional characteristics similar to biological tissues with a
range of physical and chemical properties. Adhesive hydrogels
1
have been used in different applications such as regenerative
2
3
4,
medicines, wound healing, and tissue engineering.
5
Hydrogels with 3D networks can mimic the structure and
functions of tissue microenvironment for monitoring cellular
Functionalized adenine (3) and adenine-dopamine adduct
(
1
6) were synthesized using a reported procedure (SI, Scheme
B). Polymers, P1–P4 were synthesized by functionalizing PAA
or Alg polymer with 3 and 6 using the literature procedure
6
,7
behaviour and properties. Cells showed different growth
patterns in two dimensional (2D) and three dimensional (3D)
cell culture models. Despite the fact that 3D cell culture is
closer to an in vivo model, it is not widely used as a cellular
model owing to many practical difficulties, which include poor
reproducibility and low performances.
Natural biopolymers are considered as good candidates for
preparing hydrogels for biomedical applications.
modifications are necessary to introduce appropriate
functional groups to improve the interactions between the gel
and cell surface. Nucleobases present in cellular DNA play an
important role towards controlling overall health and functions
of living tissues.12 Nucleobases and their derivatives form
functional supramolecular structures through intermolecular
hydrogen bonds.13 Even though catechol groups show active
roles in many biological systems, the chemistry of catechol
derivatives is not well explored in the design of new
8
19, 20
(Figure 1, Scheme S1 C, D).
All final polymers, P1–P4 are
characterized using NMR and UV-Vis spectroscopy where the
appearance of new peaks in the aromatic region corresponds
to the incorporation of adenine and dopamine moieties on the
9
polymer backbone (Figure S10-S11).
1
0, 11
HO
Chemical
OH
HO
NH2
N
NH2
N
NH2
N
NH2
OH
N
N
N
N
N
N
HN
N
N
N
N
NH
N
N
N
HN
HN
HN
O
n
OH
O
HN
O
n
OH
O
O
OH
O
COOH
m
OH
O
O
OHO
COOH
m
OH
HO
O
HO OH
HO
O
n
O
n
O
OH
O
OH
m
m
P1
P2
P3
P4
Figure 1. Molecular structures of synthesized polymers P1-P4.
The degree of conjugation is calculated using NMR spectra
of the polymers (P1-P4) by taking the ratio of integration of
adenine’s or dopamine hydrogen peaks in the aromatic region
to the C-H peaks of the polymer backbone. The data show a
a. Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543.
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur, Uttar
Pradesh 208016, India.
17
b.
Electronic Supplementary Information (ESI) available:See DOI: 10.1039/x0xx00000x
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low degree of functionalization (0.1 %) of adenine or adenine– conditions.23, 24 The adhesive behaviour of P2 gel wViietwhAartdicleenOinnliene-
dopamine adducts on the polymer backbone for P1&P2. The dopamine adduct as anchors to the surDfOacI:e10w.10a3s9e/Dx0aCmCi0n4e9d09iCn
functionalized polymers were then cross-linked to form a gel, detail using various substrates. The gel was placed on top of
2
1
as confirmed by tube upside-down test (Figure S12&S13).
various substrates for 5s and then it was lifted up for checking
The gels from P1&P2 are transparent and the observed light the adhesion (Figure S16). It showed excellent adhesivity to all
yellow colour of the P2 gel is due to dopamine oxidation hard and soft substrates including biological samples such as
(Figure 2A). The freeze-dried hydrogels showed porous human and pork skin (Figure S16). Also, the gel did not leave
morphologies in SEM micrographs (Figure S14).
any residue when peeled off from the surfaces implying good
cohesive interactions (Figure S17). The pork skin was wet,
moist and greasy, especially from the inside, but the P2
hydrogel stuck to pork skin surface strongly suggesting the
adhesion ability to the wet surfaces. To validate the findings,
quantification of the adhesive strength of P1&P2 gels with
different substrates such as glass, aluminium and bio-tissues
like pork skin were done using texture analysis method (Figure
S18, Video S1). Adhesiveness was obtained with respect to
work done or force required to detach the probe from the
samples and expressed as a negative value (Figure 3A).
Adhesive strength decreases in the order of P2>P1>PAA,
reflecting the strong interaction between the functional
groups on the polymer backbone and different substrates
2
5
(Figure 3B). P2 has adenine-dopamine adduct on the backbone
to impart adhesive interactions with substrates while P1 only
has adenine groups. The adhesive strength of the gels on glass
surface was low for PAA (-2.2±0.6 g.s), followed by P1 (-11±2
g.s) and P2 with highest value (-28.7±6.5 g.s) (Figure 3B).
Figure 2. Transparent hydrogels (A) prepared from P1 and P2. Swelling ratio curve (B)
for P1 (——), P2 (——) and pure PAA (—▲—). Rheological properties – change in
storage modulus G’ for P1 (——) and P2 (——) and change in loss modulus G” for P1 Similar trend was also observed in the case of aluminium and
(——) and P2 (——) with respect to time (C) and frequency (D)
pork skin substrates. Polymer P2 showed highest adhesive
strength of -196±15 g.s followed by P1 (-98.33±10.04 g.s) on
Swelling ratio of hydrogels (5% w/v) was investigated by pork skin (Figure 3B). The same trend was observed for the
incubating them in phosphate buffered saline (PBS) solution hardness and cohesive strength of P1 and P2 (Figure 3C&D).
for 96 hr (Figure 2B). Swelling ratio curves indicate that P1 and
P2 hydrogels swelled with a same rate initially, but P2 showed
a slightly higher swelling rate after 24 hr, while PAA showed a
relatively lower swelling rate (Figure 2B). The presence of polar
groups such as adenine and dopamine plays a significant role
towards interacting and stabilizing water molecules as swelling
ratio decreased in the order of P2>P1>PAA.
The viscoelastic nature of hydrogels (5% w/v) was studied
to understand the role of dynamic stiffening of hydrogels
2
2
under different environments. The changes in G’ (storage
modulus) and G” (loss modulus) at a fixed frequency of 1 Hz
for 5 min shows a higher value of G’ throughout the time
period than G” showing an elastic nature of hydrogels from
both P1 and P2 (Figure 2C). Moreover, the same trend was
observed for angular frequency range from 0.1-100 rad/s
(Figure 2D). Both gels showed consistent stability under low
and high strain (Figure S15). The elastic modulus at 1 rad/s for
Figure 3. Schematic representation of the graph obtained from the texture analysis (A),
P2 (188 Pa) was higher than P1 (31 Pa), which can be adhesive strength (B) of the PAA gels on glass (), aluminium () and pork skin (),
hardness of the gels (C) and cohesive strength of the gels (D).
attributed to the increase in hydrophobic and hydrophilic
interactions among the polymer chains due to the
To understand the biocompatibility of gels, BHK-21 cells
were cultured (2D culture) in the presence of hydrogels
prepared from P1, P2 and PAA polymers. Interestingly, cell
viability was increased within 24 hr in the presence of gels, as
compared to control well with no added gel (Figure S19). P2
showed the highest proliferation followed by P1, which
incorporation of adenine-dopamine adduct on the polymer
backbone (Figure S12). The results also suggest the soft nature
of the gels, which mimic similar properties of the extracellular
matrix (ECM).
Nucleobase incorporated hydrogels are known for strong
interactions with diverse substrates under various
2
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suggests the active role of adenine-dopamine adduct on the
backbone of P2.
Cell Viability experiments showed an increase in cell
density (BHK-21) within 24 hr, owing to increased proliferation
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DOI: 10.1039/D0CC04909C
It has been reported that a mixture of polyacrylamide on mixed P2P4 (upto 7-8 folds) & P1P3 gel than the control
(
PAAm) and Alg form hydrogel with increased stability and (without gel) and individual polymer components (Figure S22),
2
6, 27
adhesive property than individuals.
To evaluate the effect suggesting a combined effect of Alg polymer derivatives and
of mix polymer hydrogel on proliferation, Alg polymers functionalized PAA. In order to understand the versatility of
incorporated with 3 (P3) and 6 (P4) were synthesized (Figure 1, the gels, we also explored the proliferation of A431 human
SI Scheme 1C).1
9, 20
They were successfully characterized using skin cancer cells. Normal 2D cell culture on a cover slip was
NMR & UV spectroscopic techniques where the new peaks in employed as a control. The cell viability (2D culture) results
the aromatic region were originated because of showed an increase in cell density up to 3-4 folds for P2P4 gel
functionalization on Alg polymer backbone (Figure 4A, Figure followed by P2 gel within 24 hr (Figure 5A). The results are
S20). P3 showed 0.9±0.2 % and P4 with 0.4±0.05 % degree of complemented with the observed increase in ATP production
substitution by NMR.1
7
during the same time period (Figure 5B). The gels seeded with
cells were incubated for 24 hr, removed from the culture
media and cell morphologies & distribution were examined
using confocal microscopy. The morphology of the cells did not
change in the presence of P2P4 or P2 gel (Figure S23).
Figure4. UV-Vis spectra of polymers P3 (——), P4 (—▲—) and Alg (——) polymers
(A), optical image of P2P4 (1:1) gel (B), rheological properties -change in storage
modulus G’ (——) and in loss modulus G” (——) for P2P4 hydrogel with respect to
time (C) and frequency (D) along with loss factor for hydrogel tan () (——).
Figure 5. Cell viability (A) and ATP production (B) assays for A431 cells in presence of
gels P2P4 (), P2 () and control () in 2D cell culture. Cell viability (C) and ATP
production (D) in presence of gels P2P4 (), P2 (), PAA () and in the absence of gel
() inside a 3D-culture of A431 skin cells.
After successful characterization, the functionalized Alg
polymers (P3&P4) were blended with functionalized PAA
The growth and penetration of cells inside the hydrogel
(P1&P2) and cross-linked to prepare P1P3 and P2P4 gels.
was examined using z-stack imaging (Videos S2 and S3),
indicating that cells grew inside the 3D- gel mimicking the
biological environment. We also quantified the proliferation
based on the analysis of intensity of nuclear staining using
Hydrogel prepared from adenine-dopamine adduct
incorporated PAA and Alg polymers (P2P4, 1:1) was not
transparent (Figure 4B) owing to the presence of Alg polymer
2
8
and dopamine in the mixture. Similarly, a 1:1 mixture of
polymers P1&P3 was also prepared to form gel in the same
way and used for comparison. Rheological studies showed an
increase in elastic modulus of P2P4 gel (255 Pa) as compared
to P2 (188 Pa) at an applied frequency of 1 rad/s. The values of
G’ was consistently higher with respect to time, frequency and
shear strain, as compared to the values of G” signifying its
elastic nature (Figure 4C&D; Figure S21A). Moreover, the loss
factor tan  was below 0.5 for all frequencies tested indicating
2
9
image J analysis of the confocal micrographs. This showed an
increase in intensity of nuclear stain with time, which further
proves enhancement in proliferation of skin cells (Figure S24).
Hydrogels are excellent scaffolds for 3D-cell culture
experiments because of their porous and viscoelastic
characteristics which mimics the 3D-microenvironment of
3
0
extracellular matrix (ECM). We used a previously reported
method for preparing 3D-cell culture of hydrogels.3
1, 32
Here
we premixed A431 cells with polymer solution and incubated
for gelation at 37 °C for 6-7 hr (Figure S25). The insitu gelation
was confirmed by upside-down tube method. Before
incubation, it was free flowing viscous liquid but after
incubation, the polymer solution was gelled nicely with no flow
characteristics (Figure S26). Cell density was measured at
different time points and P2P4 gel showed maximum
2
3
an excellent viscoelastic nature of the P2P4 gel (Figure 4D).
Swelling ratio of the P2P4 gel showed an increased rate of
swelling for the first 24 hr and reached equilibrium near 72 hr
in PBS (Figure S21B). Hydrogel formation was confirmed with
the help of SEM analysis where the fully swollen freeze-dried
hydrogel showed typical network gel morphology (Figure S21
C&D).
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proliferation followed by P2 and then PAA (Figure 5C). Normal
control was also set up without hydrogel for comparison. Cell
viability was increased to more than 2 times than the control
Conflicts of interest
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DOI: 10.1039/D0CC04909C
“There are no conflicts to declare”.
Notes and references
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1
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We gratefully thank Madam Jiang Xiaohui, Ms. Huang Min
and Prof Yang Hongshun at the Food Science and Technology
centre, NUS for their guidance regarding texture analysis and
rheological measurements. We gratefully acknowledge
funding support from the National University of Singapore (A-
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43-000-A76-113) and PhD scholarship through IITK-NUS joint
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degree program. Sandeep Verma thanks SERB for JC Bose
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TOC graphic
Bioinspired Adenine-Dopamine Immobilized Polymer Hydrogel Adhesive for
Tissue Engineering
Saurabh Joshi, Gomathi Mahadevan, Sandeep Verma, Suresh Valiyaveettil*
*
Transparentadhesive gel
HO
HO
NH2
N
N
HN
N
N
HN
O
Cell Proliferation
Adenine – dopamine adduct incorporated polyacrylic acid forms hydrogels with enhanced adhesiveness,
transparency, biocompatibility and promote cell proliferation in in vitro models within 24 hr.