4.1 Cross-Linking of Synthetic Polymers Through Boronic
Ester Linkages
Diol-containing synthetic polymers such as poly(vinyl alcohol) (PVA)-, poly(dopamine) (PDA)-, and linear poly(ethylene glycol) (PEG)-based derivatives have been
widely used to obtain hydrogels with boronic ester bond-based linkages. Also, the
boronic acid functional group can be incorporated to polymer backbone through
polymerization of boronic acid-containing monomers. The chemistry is not new, and
boronic ester chemistry has been used for many years to obtain cross-linked polymers. For example, in 1991, Kitano reported a polymeric material obtained by crosslinking PVA and poly(N-vinyl-2-pyrrolidone) with pendent phenylboronic acid
(PBA) moieties which undergoes sol-gel transition in a glucose-sensitive manner
[37]. But in recent years, due to renewed interest in stimuli-responsive materials, the
chemistry has resurfaced and has been a topic of intensive research over the past few
years. For example, in 2011, He et al. reported a hydrogel formed through boronatecatechol complexation [38]. A hydrogel was synthesized by cross-linking
1,3-benzenediboronic acid with catechol-functionalized four-arm PEG under basic
conditions (pH 9). Gel-to-sol transition was pH dependent, as demonstrated by
lowering the pH to 3.0, after gel formation at pH 9.0. Self-healing of gel was
investigated by rheological measurements, where G
0 decreased and crossed with
G
00 under high strain (1,000%) and recovered back upon decreasing the strain to 5%.
However, formation of boronate ester bond under harsh alkaline condition limits
its application in biomedical fields. A solution to such problem was proposed in an
early report, in 2007, where Kiser and coworkers reported pH-sensitive hydrogels
that can be suitable for biological applications such as drug delivery [39]. They
optimized the gelation at physiological pH by using salicylhydroxamic acid (SHA)
which has a higher affinity for PBA at around pH 4–5. Polymers containing PBA or
SHA were prepared by free radical polymerization of appropriate acrylic monomers
with either acrylic acid (AA) or 2-hydroxypropylmethacrylamide (HPMA). Hydrogel was obtained by mixing aqueous solutions of PBA- and SHA-containing polymers at physiological pH. The study shows that the nature of the polymeric
backbone such as neutral or charged plays an important role in the pH-based
reversibility of interchain interactions.
###Recently, Deng et al. used dynamic boronic ester cross-linking to fabricate
self-healing hydrogels at neutral and acidic pH by using 2-acrylamidophenylboronic
acid (2APBA), an intramolecular coordinating boronic acid monomer [40]. They
cross-linked the copolymer of N,N-dimethylacrylamide (DMA) and 2APBA with
two different diol-containing polymers (either PVA or a catechol-functionalized
copolymer, namely, P(DOPAAm-co-DMA)) in DI water or in a potassium
biphthalate buffer at (pH 4.0) (Fig. 16a). Internal coordination between the carbonyl
oxygen and boron helped to stabilize boronic ester at acidic and neutral pH. Visual
self-healing experiments of P(2APBA-co-DMA) hydrogel demonstrated scar disappearance within 60 min (Fig. 16b). Self-healing properties of hydrogels formed from
P(2APBA-co-DMA) and P(DOPAAm-co-DMA) or PVA at pH 4.0 were
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
265
Ester Linkages
Diol-containing synthetic polymers such as poly(vinyl alcohol) (PVA)-, poly(dopamine) (PDA)-, and linear poly(ethylene glycol) (PEG)-based derivatives have been
widely used to obtain hydrogels with boronic ester bond-based linkages. Also, the
boronic acid functional group can be incorporated to polymer backbone through
polymerization of boronic acid-containing monomers. The chemistry is not new, and
boronic ester chemistry has been used for many years to obtain cross-linked polymers. For example, in 1991, Kitano reported a polymeric material obtained by crosslinking PVA and poly(N-vinyl-2-pyrrolidone) with pendent phenylboronic acid
(PBA) moieties which undergoes sol-gel transition in a glucose-sensitive manner
[37]. But in recent years, due to renewed interest in stimuli-responsive materials, the
chemistry has resurfaced and has been a topic of intensive research over the past few
years. For example, in 2011, He et al. reported a hydrogel formed through boronatecatechol complexation [38]. A hydrogel was synthesized by cross-linking
1,3-benzenediboronic acid with catechol-functionalized four-arm PEG under basic
conditions (pH 9). Gel-to-sol transition was pH dependent, as demonstrated by
lowering the pH to 3.0, after gel formation at pH 9.0. Self-healing of gel was
investigated by rheological measurements, where G
0 decreased and crossed with
G
00 under high strain (1,000%) and recovered back upon decreasing the strain to 5%.
However, formation of boronate ester bond under harsh alkaline condition limits
its application in biomedical fields. A solution to such problem was proposed in an
early report, in 2007, where Kiser and coworkers reported pH-sensitive hydrogels
that can be suitable for biological applications such as drug delivery [39]. They
optimized the gelation at physiological pH by using salicylhydroxamic acid (SHA)
which has a higher affinity for PBA at around pH 4–5. Polymers containing PBA or
SHA were prepared by free radical polymerization of appropriate acrylic monomers
with either acrylic acid (AA) or 2-hydroxypropylmethacrylamide (HPMA). Hydrogel was obtained by mixing aqueous solutions of PBA- and SHA-containing polymers at physiological pH. The study shows that the nature of the polymeric
backbone such as neutral or charged plays an important role in the pH-based
reversibility of interchain interactions.
###Recently, Deng et al. used dynamic boronic ester cross-linking to fabricate
self-healing hydrogels at neutral and acidic pH by using 2-acrylamidophenylboronic
acid (2APBA), an intramolecular coordinating boronic acid monomer [40]. They
cross-linked the copolymer of N,N-dimethylacrylamide (DMA) and 2APBA with
two different diol-containing polymers (either PVA or a catechol-functionalized
copolymer, namely, P(DOPAAm-co-DMA)) in DI water or in a potassium
biphthalate buffer at (pH 4.0) (Fig. 16a). Internal coordination between the carbonyl
oxygen and boron helped to stabilize boronic ester at acidic and neutral pH. Visual
self-healing experiments of P(2APBA-co-DMA) hydrogel demonstrated scar disappearance within 60 min (Fig. 16b). Self-healing properties of hydrogels formed from
P(2APBA-co-DMA) and P(DOPAAm-co-DMA) or PVA at pH 4.0 were
Self-Healing Hydrogels Based on Reversible Covalent Linkages: A Survey of. . .
265