Designing Hydrogels by ATRP - In-Situ Gelling Polymers: For Biomedical Applications - page 88

( ≈ 7 wt%) as PNIPAM undergoes a sharp thermo-response [ 209 ]. When a difunc-
tional initiator containing a dynamic disulfide linkage was used, the synthesized
P(NIPAM-b-MPC-ss-MPC-b-NIPAM) copolymers formed thiol and temperature
responsive gels. Physical gelation was triggered by an increase in temperature,
while the physically crosslinked gel could be permanently degraded/dissolved
upon exposure to a reducing agent such as glutathione, making the thiol-respon-
sive injectable hydrogel a suitable anticancer drug delivery depot [ 208 ]. In addi-
tion to incorporating thiol-responsive gel dissolution, injectable thermoresponsive
hydrogels from BAB copolymers have been designed to incorporate light trig-
gered [ 213 ] or enzyme catalyzed [ 214 ] gel-sol transitions to enhance delivery of
encapsulated compounds. Recently, a phosphorylated BAB triblock copolymer
was demonstrated to be an effective scaffold for bone tissue engineering. The
copolymer was synthesized through consecutive ATRP of tert -butyl acrylate and
NIPAM, followed by hydrolytic cleavage of the esters in the acrylate block to gen-
erate a central hydrophilic poly(acrylic acid) block. O-phosphoethanolamine was
conjugated to the central A block to enhance mineralization and mimic naturally
occurring hydroxyapatite in healthy bone structures [ 215 ]. Building on the concept
of BAB triblocks, ABC triblock [ 216 , 217 ] and CBABC pentablock copolymers
[ 218 - 220 ] with various distributed chemical functionalities have also been synthe-
sized and shown to form hydrogels in situ. The presence of a third monomer can
introduce additional stimuli-responsive properties and alter the critical gelation
concentration.
Multi-arm star ( n BA n ) block copolymers with central hydrophilic A blocks
and stimuli-responsive B blocks possess lower critical gelation concentrations
than linear analogues due to extra chain entanglement and inter-micelle bridging
[ 221 , 222 ]. Conveniently, one of the primary advantages of ATRP over competing
CRP techniques is the ease with which multifunctional initiators can be prepared.
A 3-arm star diblock copolymer with a MCP core and various AMA arms was
found to form physically robust free standing gels at lower polymer concentrations
than comparable BAB triblock copolymers [ 223 ]. Depending on the ratio and type
of AMA monomer used, both thermoresponsive and pH responsive behavior was
observed. In another study, AMA was used as the core forming segment in a 4-arm
star copolymer, and gelation and gel dissolution was also found to be pH and tem-
perature dependent [ 224 ].
Due to concerns over potential cytotoxicity of poly(N-substituted acrylamide)
and poly(amino methacrylate), methacrylates with pendant ethylene oxide units
(OEOMA) have been investigated as a class of promising alternative monomers
to synthesize polymers with high biocompatibility and thermoresponsive behav-
ior. A series of 4-arm star diblock copolymers containing OEOMA segments were
synthesized from a PEO macroinitiator. By tuning the ratio of different OEOMA
monomers, the LCST response of the arms occurred below body temperature,
allowing for the formation of biocompatible free standing gels in various buffer
solutions and cell culture media [ 225 , 226 ].
Enhanced gel degradation can also be incorporated through the use of bio-
degradable polymers. A 4-arm diblock copolymer containing a biodegradable