Introduction to In Situ Forming Hydrogels for Biomedical Applications - In-Situ Gelling Polymers: For Biomedical Applications - page 8

Polymers containing well balanced hydrophilic blocks and hydrophobic blocks
can physically crosslink as temperature increases by forming associations of
hydrophobic domains. PEG has been used as a hydrophilic block in most of the
thermogelling systems. Thermogelling systems that show sol-to-gel transition at
around physiological temperature have been widely developed for injectable bio-
medical applications. At low temperature, thermo-sensitive polymer aqueous solu-
tion is easy to mix with cells, drugs, and/or bioactive molecules, followed by an
injection of the mixture to target site to form a hydrogel. The target site can be
a subcutaneous layer for a protein drug delivery, a tumor tissue for an anticancer
drug delivery, or a damaged defect for tissue regeneration. As thermogelling poly-
mers, (1) polyacrylates: NIPAAm copolymers and mono and dilactate substitute
poly(2-hydroxypropyl methacrylamide), (2) polyesters: PEG/PLGA, PEG/poly( ʵ -
caprolactone) (PCL), and PEG/poly( ʵ -caprolactone-co-lactide) (PCLA) block
copolymers, (3) poly(ester urethane) (poly(1,4-butylene adipate) (PBA)/PEG/PPG
connected by hexamethylene disiocyanate, (4) natural polymer and its derivatives
(chitosan/ ʲ -glycerol phosphate, chitosan-g-PEG, HA-g-PNIPAAm, (5) polyphos-
phazenes, (6) Pluronic ® and its derivatives, (7) poly(trimethylene carbonate), and
(8) polypeptides: elastin-like (VPGVG) polypeptide (ELP), silk-like (GAGAGS)
polypeptides, polyalanine (PA), poly(alanine-co-phenylalanine) (PAF),
poly(alanine-co-leucine) (PAL), etc. have been developed [ 48 - 61 ]. Polypeptide-
based thermogelling systems have several advantages compared with polyester-
based hydrogels. (1) During gel degradation, polypeptide thermogels maintain
neutral pH since degradation products are neutral amino acids, while pH of poly-
ester thermogels decreases due to their acidic degradation products. Decrease in
pH can be a problem for biomedical applications, since it can decrease cell viabil-
ity or protein drug stability. (2) Enzyme-sensitive degradation of the polypeptide-
based hydrogel systems provides a storage stability of the encapsulated material
in vitro [ 62 ]. (3) Polypeptides have unique secondary structures including ʱ -helix,
ʲ -sheet, triple helix, and random coil, allowing various nano-assemblies followed
by sol-to-gel transition. These nano-assemblies can give unique nanostructures in
the hydrogels. Thus, polypeptide-based hydrogels can provide biomimetic ECMs
with various nanostructures that can affect proliferation and/or differentiation of
encapsulated cells [ 3 , 63 ].
Crosslinking by addition of ions provides reversible hydrogels. Alginate
hydrogel formation using calcium ions can be carried out at mild condi-
tion of room temperature and physiological pH. Therefore, alginate gels have
been used for encapsulating cells and protein drugs [ 64 ]. Salts in media also
triggered MAX8 (VKVKVKVKV D P L PTKVEVKVKV-NH 2 ) and HLT2
(VLTKVKTKV D P L PTKVEVKVLV-NH 2 ) peptides to fold into a ʲ -hairpin confor-
mation that induced hydrogel formation [ 65 ].
Inclusion complexes between cyclodextrins (CDs) and guest molecules induce
physical associations to form physical hydrogels. There are three subtypes of ʱ -,
ʲ -, ʳ -CDs consisting of 6, 7, and 8 glucopyranose units, where the internal diam-
eter of the cavity are 5.7, 7.8, and 9.5 Å, respectively [ 66 ]. Different-sized guest
molecules can selectively insert into the inner cavity of CD with proper diameter.