Biomedical Engineering Reference
In-Depth Information
slower compared to a freshly prepared hydrogel, as also shown in Fig.
5
c. To
conclude these in vitro experiments, cyano-fluorescent proteins were encapsulated
in the same hydrogels. The release of these proteins shows that hydrogels based on
long PEG chains (20 kDa) have a slower release than gels based on short chains
(10 kDa). The variation of the alkyl-spacer length also influences the release of
the proteins; the longer the spacer, the slower the delivery. With these results in
hand, Meijer and coworkers conducted in vivo studies on rats. These studies were
performed with a gel loaded with a bone morphogenetic protein (BMP7) that was
injected underneath the kidney capsule of rats, as shown in Fig.
6
. Seven days after
implantation, the hydrogels were completely eroded and the kidneys were exam-
ined by histology. The amount of myofibroplasts was estimated, showing no signs
of any immune reaction towards the hydrogel.
With this latter work, Meijer and coworkers introduced the first synthetic pol-
ymeric hydrogel based on supramolecular crosslinking of UPy-modified PEG.
These materials are biodegradable, non-immunogenic, and tunable. In a follow-
up publication, Meijer and coworkers investigated the rheological properties in
greater detail and exploited this system further, primarily in view of application for
protein delivery into kidneys [
93
].
3 Hydrogels Crosslinked by Metal Complexation
A hydrogel based on metal-complexation crosslinking is formed when ion com-
plexes interconnect polymer chains that are functionalized with suitable ligand-
moieties. Depending on the metals and ligands used, the resulting coordinative
bonds can exhibit binding energies of up to 400 kJ mol
−
1
[
77
]; as a result, this
interaction allows for the design of hydrogels that exhibit stabilities ranging
from very labile to covalent-like [
33
]. Hydrogels formed by metal-ligand com-
plexation most commonly base on ions such as Mn, Fe, Co, Ni, Cu, Zn, Ru, Ag,
Cd, Os, Ir, and Pt in their low oxidation states (
+
2 or
+
3). In a seminal series
of work, Schubert and co-workers investigated the characteristics of differ-
ent metal ions using terpyridine-modified polymers as the ligands, showing that
Fe-crosslinked gels are thermally less stable than Ru-crosslinked gels [
94
]. In
addition to terpyridine, other ligands such as benzimidazolpyridines [
95
,
96
],
bipyridines [
97
,
98
], or catechols [
99
,
100
], have been applied to prepare gels.
The use of toxic transition metal ions like Ag, Cu, or Cd limits the use of these
gels to applications in materials science. For more demanding biomedical appli-
cations, biologically inert metal ions or ions that are already present in the human
body, including Mg, Ca, Fe, Zn, Pt, and Au, must be used [
45
,
101
].
The most prominent example of a biopolymer hydrogel based on crosslinking
by metal complexation is alginate. It is a polysaccharide composed of mannuronic
and guluronic acid in three different fashions: blocks of guluronic acid, blocks
of mannuronic acid, and alternating blocks of both. A hydrogel is formed when
multivalent ions are added to a solution of algic acid in water, interacting with its
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