Hydrogels: Biomaterials for Sustained and Localized Drug Delivery
225
greater depths with lack of light intensity, and absence of photo-initiator has gained
much attention [139]. Thiol and acrylate reaction is one of the extensively employed
Michael addition reactions that can be coupled with photopolymerization, which is
referred to as mixed-mode polymerization. It can yield tunable polymeric network
formation and degradation by adjusting the thiol and acrylate ratio. Thiol groups
also facilitate the post-polymerization of the hydrogel. Poly butadiene and poly (allyl
methacrylates) functionalized with thiol can undergo photocatalytic redox reaction
in visible light to form linear polymers by step-growth addition reaction [127, 85,
121].
ii. Crosslinking by Enzyme catalyzed reaction
Enzyme catalyzed crosslinking offers rapid in situ gelation with a possibility
of tuning gel formation by controlling enzyme concentration under physiological
conditions. Many kinds of enzymatic crosslinking methods are identified, such as
amide linkage between carboxamide and amine groups in the presence of transglutaminase (TG); horseradish peroxidase (HRP) catalyzed coupling of aniline, phenol
and its derived tyramine catalyzed by hydrogen peroxide. Enzymatically conjugated collagen with tyramine (Collagen- Ph) in the presence of HRP and H 2 O 2
has been employed for constructing novel vascularized tissue [86]. This hydrogel
encapsulated with bone marrow-derived mesenchymal stem cells (MSCs) and with
human blood-derived endothelial colony-forming cells (ECFCs). The encapsulation
improved prolonged MSC differentiation in the mouse as model organism after one
month of implantation [123–87].
iii. Crosslinking by “Click chemistry.”
Chemical reactions that favor high yield under mild conditions, lesser by-products,
and increased specificity and selectivity are termed as “click” reactions. This reaction
highly depends upon the functional groups of the polymeric materials for hydrogel
fabrication. Classical click chemistry reactions are discussed as follows.
Diels Alder (DA) reaction is a one-step, highly selective, cycloaddition (4 + 2)
between a dienophile (maleimide) and a diene (furan), that can occur in the absence
of any initiators, catalysts and coupling agents. Polymers are customized accordingly
with furan or furan derivatives to react with poly (ethylene glycol) dimaleimide for
hydrogel formation [43]. Modifications are further being made to increase the DA
reaction rate at physiological conditions, such as replacement of furan as methylfuran
[189].
Schiff base formation is a condensation reaction between formyl or carbonylcontaining derivative and primary amines in the presence of catalysts like alkaline
earth metal ions to form imine linkages. It has been extended to form injectable in situ
gelling hydrogel as aldehyde end can adhere to tissues or organs [130]. Schiff linkages
can be considered to be pseudo- covalent bonds that facilitate uncoupling and recoupling of these linkages in polymeric networks result in self-healing capability. The
amino group of the acrylamide modified chitin (AMC) and dialdehyde yield oxidized
alginate for self-healable polymeric hydrogel. The molar ratio of the monomers and
the microenvironment pH largely influence hydrogel formation [38].
225
greater depths with lack of light intensity, and absence of photo-initiator has gained
much attention [139]. Thiol and acrylate reaction is one of the extensively employed
Michael addition reactions that can be coupled with photopolymerization, which is
referred to as mixed-mode polymerization. It can yield tunable polymeric network
formation and degradation by adjusting the thiol and acrylate ratio. Thiol groups
also facilitate the post-polymerization of the hydrogel. Poly butadiene and poly (allyl
methacrylates) functionalized with thiol can undergo photocatalytic redox reaction
in visible light to form linear polymers by step-growth addition reaction [127, 85,
121].
ii. Crosslinking by Enzyme catalyzed reaction
Enzyme catalyzed crosslinking offers rapid in situ gelation with a possibility
of tuning gel formation by controlling enzyme concentration under physiological
conditions. Many kinds of enzymatic crosslinking methods are identified, such as
amide linkage between carboxamide and amine groups in the presence of transglutaminase (TG); horseradish peroxidase (HRP) catalyzed coupling of aniline, phenol
and its derived tyramine catalyzed by hydrogen peroxide. Enzymatically conjugated collagen with tyramine (Collagen- Ph) in the presence of HRP and H 2 O 2
has been employed for constructing novel vascularized tissue [86]. This hydrogel
encapsulated with bone marrow-derived mesenchymal stem cells (MSCs) and with
human blood-derived endothelial colony-forming cells (ECFCs). The encapsulation
improved prolonged MSC differentiation in the mouse as model organism after one
month of implantation [123–87].
iii. Crosslinking by “Click chemistry.”
Chemical reactions that favor high yield under mild conditions, lesser by-products,
and increased specificity and selectivity are termed as “click” reactions. This reaction
highly depends upon the functional groups of the polymeric materials for hydrogel
fabrication. Classical click chemistry reactions are discussed as follows.
Diels Alder (DA) reaction is a one-step, highly selective, cycloaddition (4 + 2)
between a dienophile (maleimide) and a diene (furan), that can occur in the absence
of any initiators, catalysts and coupling agents. Polymers are customized accordingly
with furan or furan derivatives to react with poly (ethylene glycol) dimaleimide for
hydrogel formation [43]. Modifications are further being made to increase the DA
reaction rate at physiological conditions, such as replacement of furan as methylfuran
[189].
Schiff base formation is a condensation reaction between formyl or carbonylcontaining derivative and primary amines in the presence of catalysts like alkaline
earth metal ions to form imine linkages. It has been extended to form injectable in situ
gelling hydrogel as aldehyde end can adhere to tissues or organs [130]. Schiff linkages
can be considered to be pseudo- covalent bonds that facilitate uncoupling and recoupling of these linkages in polymeric networks result in self-healing capability. The
amino group of the acrylamide modified chitin (AMC) and dialdehyde yield oxidized
alginate for self-healable polymeric hydrogel. The molar ratio of the monomers and
the microenvironment pH largely influence hydrogel formation [38].