Multivalent H-bonds for self-healing hydrogels

Article abstract of DOI:10.1039/c2cc34701f

UPy is used as a reversible and dynamic crosslinker to prepare hydrogels that are injectable and undergo rapid self-healing in response to damage.

Full text of DOI:10.1039/c2cc34701f

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COMMUNICATION
Multivalent H-bonds for self-healing hydrogelsw
´
Jiaxi Cui and Aranzazu del Campo*
Received 1st July 2012, Accepted 23rd July 2012
DOI: 10.1039/c2cc34701f
UPy is used as a reversible and dynamic crosslinker to prepare
hydrogels that are injectable and undergo rapid self-healing in
response to damage.
Self-healing materials possess the ability to repair themselves
in response to damage leading to a new route towards safer,
longer-lasting products.1 Self-healing mechanisms in bulk
polymer materials are either based on the release of repair
agents upon damage,1 or on the inclusion of latent molecular
functionalities in the polymer structure that trigger repair via
thermally reversible reactions, hydrogen bonding, ionomeric
arrangements, or molecular diffusion and entanglement.2
Recently self-healing properties have been extended to hydrogels.
Different reversible molecular interactions have been exploited for
this purpose: electrostatic interactions between polyelectrolytes,3
molecular-recognition (protein–protein4 and host–guest5 inter-
actions), metal coordination,6 hydrophobic7 or p–p stacking8
association, dynamic chemical bonds9 or molecular diffusion
and entanglement.10
Scheme 1 Chemical structure of the copolymer containing DMAEMA
and SCMHBMA (A) and the schematic model of self-healing and
stretching of the hydrogel formed by the copolymer (B).
Surprisingly, hydrogen bonds, being one of the common
mechanisms used in bulk self-healing materials and ubiquitous
in living systems,11 have rarely been exploited as a repairing
mechanism for hydrogels. Very recently a branched covalent
crosslinked hydrogel containing amide and carboxylic groups
in the branches has shown self-healing properties based on the
H-bonds between these groups.13 The self-healing properties
of poly(ethyleneglycol) based hydrogels containing 2-ureido-4-
pyrimidone (UPy) as end groups have also been recently
mentioned, though only poor experimental verification has
been reported.12 2-Ureido-4-pyrimidone (UPy) can dimerize
via quadruple H-bonding (>106 M in CHCl3)14 and is one of
the most commonly used units to build up supramolecular
(co)polymers11 and reversible networks.15 In this article we
exploit the associated multivalent H-bonds of the UPy unit to
form stable crosslinked hydrogels by copolymerization of a
UPy-functionalized building block with different water soluble
monomers. The resulting materials gelify without the need of
covalent bonds by dimerization of self-complementary UPy
units. This property facilitates processability of the materials,
making them stretchable and injectable. By incorporating UPy
units into different backbones multiresponsive self-healing
hydrogels were obtained.
Scheme 1A presents the chemical structure of the copolymer
containing two different components: 2-(dimethylamino)-
ethyl methacrylate (DMAEMA) and 2-(3-(6-methyl-4-oxo-1,4-
dihydropyrimidin-2-yl)ureido)ethyl methacrylate (SCMHBMA).
DMAEMA is the main component of the chain and confers
water solubility and temperature response.16 The SCMHBMA
monomer contains UPy units in the side chain, able to form
dimers by self-complementary H-bonding. The expected self-repair
and stretching ability of the system as a consequence of the
presence of UPy unit are depicted in Scheme 1. Dynamic
assembly and disassembly of UPys should enable in situ
recovery in response to damage and chain reorientation along
the stretching direction.
The SCMHBMA monomer was obtained by reaction of
6-methylisocytosine and 2-isocyanatoethyl methacrylate
(Scheme S1 in ESIw).17 Its 1H-NMR spectrum in CDCl3 showed
NH proton signals at 13.0, 12.0, 10.5 ppm, indicative of extensive
hydrogen bonding (Fig. S1 in ESIw).14 Copolymerization of
DMAEMA–SCMHBMA was carried out in 1,4-dioxane at
70 1C with azodiisobutyronitrile (AIBN) as an initiator.
A copolymer with an average molecular weight Mn = 3.8 ꢀ
104 Da was obtained with high yield (90%). The feed molar
ratio of DMAEMA–SCMHBMA used for polymerization was
Max-Planck-Institut fur Polymerforschung, Ackermannweg 10,
¨
Mainz 55128, Germany. E-mail: delcampo@mpip-mainz.mpg.de
w Electronic supplementary information (ESI) available: Experimental
procedure for polymer synthesis and details of NMR. See DOI:
10.1039/c2cc34701f
c
9302 Chem. Commun., 2012, 48, 9302–9304
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0.92/0.08 and resulted in a copolymer composition of 90 mol%
DMAEMA and 10 mol% SCMHBMA as calculated by
1H NMR spectroscopy (Fig. S2 in ESIw). A low content of
SCMHBMA unit was necessary in order to retain water
solubility of the copolymer at room temperature, since the
lower critical solution temperature (LCST) of PDMEAMA
decreases with the addition of hydrophobic components.18
The resulting copolymer maintained the temperature response
of PDMAEMA and showed a LCST of 40 1C at pH 8
(determined by a turbidity experiment in a 20 mg mLꢁ1 solution),
lower than the LCST of the PDMAEMA homopolymer at the
same pH (50 1C).16
The DMAEMA–SCMHBMA copolymer was soluble in water
at acidic pH and rendered viscous solutions at a concentration of
0.2 g mLꢁ1. Addition of aqueous NaOH to increase the pH to
>8 induced gelation of the solution, suggesting dimerization of
the UPy units in water and formation of a 3D network. In order
to demonstrate that the UPy units were responsible for hydrogel
formation, we evaluated the binding ability of the copolymer to a
UPy-modified surface via quartz crystal microbalance (QCM)
measurements. This technique can monitor the gravimetric and
viscoelastic changes at the surface by the shifts in the frequency
(Df) and dissipation (DD). A UPy-based silane coupling agent
(Fig. 1A) was used for functionalisation of a silica surface
(Scheme S2 in ESIw). In this molecule the photocleavable group
o-nitrobenzyl is attached to the carbonyl group of the UPy
ring (caged UPy) and inhibits the self-coupling ability.19 Light
exposure removes the cage and generates a UPy functionalized
surface able to bind to the copolymer. Fig. 1B presents the Df
and DD of the crystal modified with caged UPy during
incubation with a solution of DMAEMA–SCMHBMA in
chloroform or buffer (10 mM TrisꢂHCl at pH of 8.0) and
washing. No changes in Df and DD were observed after
washing, indicating that the copolymer chains could not form
H bonds with the caged UPy at the surface. However,
incubation of the copolymer solution with the light-exposed
UPy modified QCM crystal caused a clear decrease in the
frequency that was maintained after rinsing with the solvent
(Fig. 1C). This corresponds to a mass increase at the surface
due to the fixation of the copolymer via H-bonding interactions
between the UPy units. This result also agrees with the increase
in energy dissipation observed in the D-factor, characteristic of
the growth of a soft surface layer.20 A 25 Hz frequency change
was observed in chloroform, while 14 Hz was observed in
aqueous buffer. This result indicates that UPy dimers with
slightly higher stability formed in chloroform solution.
Fig. 1 (A) The UPy-based silane coupling agent 1 and the scheme of
caged and light-exposed UPy modified surfaces. (B) Evolution of the
Df and DD of the third overtone of a caged UPy modified QCM crystal
(I) during incubation with a solution of 2 mg mLꢁ1 DMAEMA–
SCMHBMA copolymer in CHCl3 or buffer (10 mM TrisꢂHCl, pH 8)
(II) and posterior washing (III). (C) Evolution of the Df and DD of the third
overtone of a UPy modified QCM crystal (I) during incubation with a
solution of 2 mg mLꢁ1 DMAEMA–SCMHBMA copolymer in CHCl3 or
buffer (10 mM TrisꢂHCl, pH 8) (II) and posterior washing (III).
between 7 and 8 and room temperature and cut into two pieces
(Fig. 2a). Self-healing occurred in 5 min within this pH range.
This property was not observed in the PDMAEMA homo-
polymer and is attributed to the presence of reversible
H-bonding between SCMHBMA units (Scheme 1B). Self-
healing did not occur if the sample was kept above the LCST,
indicating that dimerization could be switched on and off by
changing the temperature. Fig. 2c–g show an incision in a
hydrogel film performed at 50 1C (Fig. 2c) that did not heal
after 30 min (Fig. 2d and e). When the temperature was cooled
to 20 1C and the sample was kept in a humid environment,
the incision disappeared within 2 min (Fig. 2f and g). These
results indicate that diffusion of the chains is restricted in the
collapsed state and the H bonds cannot be restored. The
combination of the temperature responsive DMAEMA chain
The presence of H-bonds as reversible crosslinks in the
hydrogel was also confirmed during mechanical stretching
and deformation of the hydrogel. Hydrogel samples at pH 8
and temperature 20 1C were stretched by pulling with tweezers.
Fiber formation was clearly observed (Fig. 2b) as a consequence
of the reversible and dynamic nature of the H-bonding that
allows and reinforces reorientation and flow of the polymer
chains.21 It is important to note that this property is relevant for
injectable materials for applications in drug delivery and tissue
engineering.4 This strategy represents an alternative to physical
thermogelling hydrogels currently used for these applications.
Fig. 2a demonstrates the self-healing ability of the DMAEMA–
SCMHBMA hydrogel. A hydrogel sample was prepared at pH
c
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Chem. Commun., 2012, 48, 9302–9304 9303

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of multivalent H-bonds cross-linked hydrogel materials with
thermo-gated recovery ability. In addition, the physical hydrogel
flows and stretches under mechanical strain, representing an
alternative to physical thermogelling hydrogels for injectable
materials for biomedical applications.
Notes and references
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Fig. 2 Demonstration of the self-healing (a, c, d, e, f, g) and the
stretching (b) properties of the DMAEMA–SCMHBMA hydrogel at
pH 8. The gel in (a) and (b) was coloured with methyl blue for better
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regulated self-healing mechanism.
The self-healing ability was also tested in covalently cross-
linked DMAEMA–SCMHBMA gels prepared by copolymer-
ization with N,N0-methylene bisacrylamide. In this case two
hydrogel samples were prepared independently and brought
into contact. As they touched each other, self-healing occurred
immediately (movie in ESIw). The ‘‘glued’’ hydrogel withstood
stretching, shaking and overload stretching without visible damage
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methacrylate (HEMA), 2-(2-methoxyethoxy)ethyl methacrylate
(MEO2MA), N-isopropylacrylamide (NIPAm), and N,N0-
dimethylacrylamide (DMAA) were prepared. The copolymers
with HEMA, MEO2MA and NIPAm presented similar
self-healing behaviour, demonstrating that the recovering
ability of UPy multivalent H-bonds can be applied to different
materials. The DMAA–SCMHBMA hydrogel was brittle and
did not self-heal. Additional work will be done to clarify the
limitations of the system.
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In conclusion, UPy-based monomers can form self-
complementary H-bonds in an aqueous environment and be
used as a reversible and dynamic cross-linker to obtain
supramolecular hydrogels that rapidly self-heal. The self-healing
properties conferred by the Upy unit can be coupled to the thermal
response of the polymer matrix to generate hydrogels with
thermo-regulated self-healing behaviour. This strategy could be
further extended to different commercially available monomers,
demonstrating that it is a flexible route towards self-healing
hydrogels with various functions. This is the first reported example
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c
9304 Chem. Commun., 2012, 48, 9302–9304
This journal is The Royal Society of Chemistry 2012