3.2 Cross-Linking of Natural Polymers Through
Acylhydrazone Linkages
Natural polymers bear high potential for application in regenerative medicine and
other related biomedical fields. They can be utilized as tissue engineering materials,
bone repair/replacement, dental repair/replacement, controlled drug delivery, and
skin repair materials. Natural polymers can be functionalized using various chemical
transformations to carry hydrazine, aldehyde, or ketone moieties. Recently, Li et al.
reported a hydrogel based on hydrazine-modified hyaluronic acid (HAAD), a natural
polymer widely employed for wound healing applications and benzaldehyde modified biocompatible Pluronic F127 (BAF127) that can have a potential for promoting
burn wound healing [34]. Hydrogel was synthesized in phosphate-buffered
saline (PBS) at room temperature by utilizing acylhydrazone-based linkages.
Micellization-based cross-linking was formed by telechelic aldehyde end-linked
Pluronic F127, a nonionic triblock copolymer of PEO-PPO-PEO (Fig. 15a). Another
hydrogel was also synthesized by using the same chemistry by cross-linking HA
with four-armed PEG (TPEG) with benzaldehyde terminals to compare with the
HA-az-TPEG. The continuous strain test was employed for both systems to compare
self-healing property. The strain varied between 1 and 300% at 37
C, and both Gel3
and HA-az-TPEG hydrogels demonstrated similar rapid self-healing where the
structures were collapsed under high strain and upon reducing strain to 1% G
0
restored back to 95.0% of the original values (Fig. 15b). Also, visual experiments
showing self-healing of gels by joining of hydrogel pieces were also undertaken
(Fig. 15c).
Another promising system was reported by Sharma et al., who fabricated an
injectable self-healing hydrogel for pH-responsive release of a chemotherapeutic
agent (DOX) up to 30 days [35]. Xanthan, a high molecular weight
heteropolysaccharide, was oxidized to obtain the aldehyde groups needed for
cross-linking. Hydrogel was obtained by cross-linking eight-arm PEG with oxidized
xanthan in aqueous media at 37
C through hydrazone linkages. These hydrogels
possessed excellent cytocompatibility in 2D and 3D culture of mouse fibroblasts
(NIH-3T3). Self-healing studies were carried out by visual experiments where
hydrogels were cut into two halves and put in contact at 37
C. Furthermore,
continuous strain test showed that hydrogel lost its integrity under high strain
(800%) and regained initial G
0 value upon reducing strain to 1% in an alternating
cycle for five times.
4 Boronic Ester Bond Formation Based Hydrogels
Boronic ester bonds are formed between boronic acid derivatives and 1,2- and
1,3-diols by reversible condensation reaction in aqueous media. The stability of
boronic ester bonds can be tuned by pH, and thus this reversible bond can serve as a
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
263
Acylhydrazone Linkages
Natural polymers bear high potential for application in regenerative medicine and
other related biomedical fields. They can be utilized as tissue engineering materials,
bone repair/replacement, dental repair/replacement, controlled drug delivery, and
skin repair materials. Natural polymers can be functionalized using various chemical
transformations to carry hydrazine, aldehyde, or ketone moieties. Recently, Li et al.
reported a hydrogel based on hydrazine-modified hyaluronic acid (HAAD), a natural
polymer widely employed for wound healing applications and benzaldehyde modified biocompatible Pluronic F127 (BAF127) that can have a potential for promoting
burn wound healing [34]. Hydrogel was synthesized in phosphate-buffered
saline (PBS) at room temperature by utilizing acylhydrazone-based linkages.
Micellization-based cross-linking was formed by telechelic aldehyde end-linked
Pluronic F127, a nonionic triblock copolymer of PEO-PPO-PEO (Fig. 15a). Another
hydrogel was also synthesized by using the same chemistry by cross-linking HA
with four-armed PEG (TPEG) with benzaldehyde terminals to compare with the
HA-az-TPEG. The continuous strain test was employed for both systems to compare
self-healing property. The strain varied between 1 and 300% at 37
C, and both Gel3
and HA-az-TPEG hydrogels demonstrated similar rapid self-healing where the
structures were collapsed under high strain and upon reducing strain to 1% G
0
restored back to 95.0% of the original values (Fig. 15b). Also, visual experiments
showing self-healing of gels by joining of hydrogel pieces were also undertaken
(Fig. 15c).
Another promising system was reported by Sharma et al., who fabricated an
injectable self-healing hydrogel for pH-responsive release of a chemotherapeutic
agent (DOX) up to 30 days [35]. Xanthan, a high molecular weight
heteropolysaccharide, was oxidized to obtain the aldehyde groups needed for
cross-linking. Hydrogel was obtained by cross-linking eight-arm PEG with oxidized
xanthan in aqueous media at 37
C through hydrazone linkages. These hydrogels
possessed excellent cytocompatibility in 2D and 3D culture of mouse fibroblasts
(NIH-3T3). Self-healing studies were carried out by visual experiments where
hydrogels were cut into two halves and put in contact at 37
C. Furthermore,
continuous strain test showed that hydrogel lost its integrity under high strain
(800%) and regained initial G
0 value upon reducing strain to 1% in an alternating
cycle for five times.
4 Boronic Ester Bond Formation Based Hydrogels
Boronic ester bonds are formed between boronic acid derivatives and 1,2- and
1,3-diols by reversible condensation reaction in aqueous media. The stability of
boronic ester bonds can be tuned by pH, and thus this reversible bond can serve as a
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
263