3 Acylhydrazone Bond Formation-Based Hydrogels
Another widely used linkage for fabrication of stimuli-responsive self-healing
hydrogels involves the acylhydrazone bond, a type of imine bond that is obtained
through the condensation of a hydrazine with an aldehyde or ketone. The
acylhydrazone bond is more stable compared to an imine bond and is regarded as
kinetically inert under neutral and basic conditions. However, under acid catalysis
acylhydrazone bond can undergo hydrolysis, exchange, and metathesis reactions
like imines [11]. In recent years, this pH-responsive chemical bond has been used to
fabricate mechanically strong, pH-sensitive self-healing materials for various biomedical applications.
3.1 Cross-Linking of Synthetic Polymers Through
Acylhydrazone Linkages
An early example of polymer gels based on dynamic acylhydrazone bonds was
reported by Chen and coworkers in 2010. Gels were prepared by mixing
bis-acylhydrazine functionalized PEO with tris[(4-formylphenoxy)methyl]ethane
in the presence of catalytic amount of glacial acetic acid in dimethylformamide
(DMF) for 16 h (Fig. 10) [27]. The pH-dependent sol-gel transition was demonstrated by using HCl and TEA and repeated for 8 cycles, but the stability of gels was
lost during the transitions as deduced from rheological tests. Visual experiments
showed that two pieces of freshly prepared hydrogels merged into one by keeping
them in contact for 7 h.
Linear or branched PEG, an FDA-approved biocompatible hydrophilic polymer,
or its derivatives are widely used to fabricate cross-linked polymeric networks due to
their high solubility both in organic and aqueous media, ease of functionalization,
and conjugation. For instance, in 2017, Wang et al. reported an ultra-stretchable,
self-healable hydrogel formed by mixing a three-armed PEO with acylhydrazine
termini (G3) and a triblock copolymer PEO99-b-PPO65-b-PEO99 (PF127) with
aldehydes at chain ends (G2) in phosphate buffer (pH 6.0) via dynamic
acylhydrazone bonds (Fig. 11a) [28]. The amphiphilic triblock copolymer formed
micelles (PF127) by self-assembling in water and acted as macro-cross-linkers. Due
to the possibility of internal rearrangement of micelles under external force,
hydrogels demonstrated improved mechanical properties and did not fracture at
the largest strain (11,700%) with a stress of 297 kPa. The pH-sensitive tensile
behavior of the hydrogels due to acylhydrazone bond was also demonstrated.
When pH value changed to 6.5 or 5, lower fracture strain and stress were observed.
Self-healing capability of the hydrogel was illustrated by using stress-strain curve. A
sample was cut into two and placed in a mold to heal for 24 h. Self-healed hydrogel
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
257
Another widely used linkage for fabrication of stimuli-responsive self-healing
hydrogels involves the acylhydrazone bond, a type of imine bond that is obtained
through the condensation of a hydrazine with an aldehyde or ketone. The
acylhydrazone bond is more stable compared to an imine bond and is regarded as
kinetically inert under neutral and basic conditions. However, under acid catalysis
acylhydrazone bond can undergo hydrolysis, exchange, and metathesis reactions
like imines [11]. In recent years, this pH-responsive chemical bond has been used to
fabricate mechanically strong, pH-sensitive self-healing materials for various biomedical applications.
3.1 Cross-Linking of Synthetic Polymers Through
Acylhydrazone Linkages
An early example of polymer gels based on dynamic acylhydrazone bonds was
reported by Chen and coworkers in 2010. Gels were prepared by mixing
bis-acylhydrazine functionalized PEO with tris[(4-formylphenoxy)methyl]ethane
in the presence of catalytic amount of glacial acetic acid in dimethylformamide
(DMF) for 16 h (Fig. 10) [27]. The pH-dependent sol-gel transition was demonstrated by using HCl and TEA and repeated for 8 cycles, but the stability of gels was
lost during the transitions as deduced from rheological tests. Visual experiments
showed that two pieces of freshly prepared hydrogels merged into one by keeping
them in contact for 7 h.
Linear or branched PEG, an FDA-approved biocompatible hydrophilic polymer,
or its derivatives are widely used to fabricate cross-linked polymeric networks due to
their high solubility both in organic and aqueous media, ease of functionalization,
and conjugation. For instance, in 2017, Wang et al. reported an ultra-stretchable,
self-healable hydrogel formed by mixing a three-armed PEO with acylhydrazine
termini (G3) and a triblock copolymer PEO99-b-PPO65-b-PEO99 (PF127) with
aldehydes at chain ends (G2) in phosphate buffer (pH 6.0) via dynamic
acylhydrazone bonds (Fig. 11a) [28]. The amphiphilic triblock copolymer formed
micelles (PF127) by self-assembling in water and acted as macro-cross-linkers. Due
to the possibility of internal rearrangement of micelles under external force,
hydrogels demonstrated improved mechanical properties and did not fracture at
the largest strain (11,700%) with a stress of 297 kPa. The pH-sensitive tensile
behavior of the hydrogels due to acylhydrazone bond was also demonstrated.
When pH value changed to 6.5 or 5, lower fracture strain and stress were observed.
Self-healing capability of the hydrogel was illustrated by using stress-strain curve. A
sample was cut into two and placed in a mold to heal for 24 h. Self-healed hydrogel
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
257