Biomedical Engineering Reference
In-Depth Information
polyacrylamide gels used in electrophoresis, with PEG-DA serving the same role
as N,N'-methylenebisacrylamide. Although free-radical crosslinking is generally
used to produce macroscopic hydrogels, micron-scale hydrogels may also be
produced and further crosslinked into modular scaffolds [14, 15].
Chemical crosslinking also occurs by reaction of two groups that each have a
functionality of one ('step growth'), a characteristic that is distinct from the chain
growth mechanism of free-radical crosslinking. Linear PEG modified with
groups that participate in step growth reactions may only form high molecular
weight linear polymers. For example, Kohn and colleagues formed such high
molecular weight PEG polymers by reacting PEG-di(N-hydroxysuccinimide)
with both amines on a carboxyl-protected lysine. After deprotection and
activation of the multiple lysine carboxyl groups along the backbone of the
PEG/lysine polymer, the high functionality chains were crosslinked using a
diamine to form a hydrogel [16]. A similar strategy was employed with a linear,
thiol-containing PEG-co-2-mercaptosuccinic acid that was then crosslinked with
PEG-divinylsulfone [17]. These examples demonstrate that linear PEG must be
reacted with molecules of higher functionality to produce hydrogels in a one-step
process. The higher functionality molecules in non-hybrid materials may be
multifunctional monomers, dendrimers, or star/multiarm polymers [5, 18-20].
Hydrogels produced by reaction of linear unmodified PEG and a small,
multifunctional isocyanate were described over twenty years ago by Rempp and
colleagues [18]. Lysine-based dendrons may also be reacted with PEG-
dialdehyde to produce hydrogels for use as a tissue sealant [20]. The availability
of high quality multiarm PEG from the NOF Corporation in the late 1990's
enabled a number of new reaction schemes, many of which were first described
by Milton Harris and colleagues [21]. Subsequently, other groups demonstrated
that nucleophilic substitution between four-arm PEG-active esters and four-arm
PEG-thiols or four-arm PEG-amines produced stable hydrogels in a one-step
reaction [22, 23]. Multiarm PEG-nucleophiles and PEG-electrophiles also may
react via Michael-type additions to form hydrogels. Reaction of multiarm PEG-
acrylate and PEG-dithiol produced hydrolytically degradable hydrogels [24],
while reaction of multiarm PEG-vinylsulfone and PEG-diamine produced stable
materials [25]. Multiarm PEG-thiol may also be oxidized to produce disulfide-
bonded hydrogels [26]. Click chemistry has recently been applied to the
synthesis of PEG hydrogels. PEG-diacetylene was reacted with tetraazide-
modified tetraethylene glycol in the presence of copper sulfate and sodium
ascorbate to produce hydrogels that were much less brittle than their
photopolymerized counterparts [27]. Bowman, Anseth and colleagues introduced
mixed-mode PEG-DA polymerization based on the transfer of free radicals to
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