1377.6.1 Hydrogels for Neuroregeneration
Hydrogels are networks composed of polymeric chains that act to mimic the
extracellular matrix (ECM). Depending on the origin of the material, hydrogels are
further stratifi ed into natural, synthetic, and/or composite materials groups. Natural
hydrogel systems include HA, collagen, chitosan, agarose, alginate, elastin, fi brino-
gen, laminin, gelatin, and more [ 223 ]. Examples of synthetic hydrogels readily
employed in biomedical applications for CNS injury include poly(ɛ-caprolactone)
(PCL), polyethylene glycol (PEG), poly(hydroxyethyl methacrylate) (PHEMA)
[ 224 ], polyvinyl alcohol (PVA), and poly[N-(2-hydroxypropyl)methacrylamide]
(PHPMA) [ 225 ]. In general, the physiochemical and structural characteristics of a
hydrogel scaffold greatly infl uence cellular response. The most important character-
istics that should be considered for any hydrogel are the hydrophilic properties,
stiffness/elasticity, ligand density, and fi ber orientation [ 226 , 227 ]. Charge is a
material characteristic that has also been well characterized and found to have sig-
nifi cant effects on neurite extension and cellular morphology. For example, the
length of neuron extension is directly proportional to the magnitude of the net posi-
tive charge on a scaffold on a certain mathematical domain [ 228 ], the high extreme
of this domain leading to growth inhibition [ 229 , 230 ]. Other studies also suggest
that positively charged hydrogels are capable of sustaining both primary nerve cells
and the neural support cells that are critical for regeneration [ 231 ]. Further, cell
behaviors are determined by the balance of cell-cell adhesion and cell-substrate
adhesion, which are a function of the hydrophilic or hydrophobic properties of the
substrate itself and any bioadhesive domains [ 232 – 236 ].
The elasticity of a substrate infl uences cellular and axonal infi ltration and tendsto have an ideal range depending on cell type and ligand. For example, PC12 neu-
rites, a rat adrenal pheochromocytoma cell line that is induced by NGF into a neu-
ronal phenotype, were found to exhibit branching and outgrowth on fi bronectin-based
substrates with a shear modulus between 10 Pa and 10 kPa [ 237 ]. While another
study found that PC12 cells on PEG substrate exhibited enhanced adhesion and
outgrowth with increasing Young’s modulus (between 75 and 400 kPa) [ 238 ].
Regardless of cell type or ligand, the literature is split on the relationship between
the elastic modulus and extent of axonal infi ltration [ 237 , 239 ]. Variation in data is
likely due, in part, to variation in ligand density. Engler et al. showed that cellular
proliferation was greatly enhanced on substrates with higher collagen densities than
on controls without collagen [ 240 ]. Similarly, Thomas et al. found that spreading
and motility of malignant astrocytes on two-dimensional (2D) polyacrylamide fol-
lowed a normal distribution with respect to both stiffness and concentration of
bound collagen [ 241 ]. Further, recent studies have highlighted the importance of
dimensionality in culture maintenance, as 3D matrices [ 239 , 242 ] have been shown
to critically affect the metabolic activity, growth, and phenotype of neural cell types
[ 243 , 244 ]. Further, cells in 2D cultures must reorganize their integrin cell surface
receptors and cytoskeleton to adapt to the planar presentation of receptor ligands,
which causes distinct dynamic and spatial differences in the distribution of cell-cell
7 Regenerative Strategies for the Central Nervous System