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proliferation, dramatic effects on the induction of neurite outgrowth and synapse
formation have been achieved using RAD16-I (Ac-HN-RADARADARADARADA-
CONH
2
) and RAD16-II (Ac-HN-RARADADARARADADA-CONH
2
) that readily
self-assembled into hydrogels when exposed to cell culture media or salt solution
(Holmes et al. 2000). A mutant peptide KLD-12 (Ac-HN-KLDLKLDLKLDL-
CONH
2
) was found to promote increased extracellular matrix (ECM) production and
chondrocyte proliferation (Kisiday et al. 2002).
Despite the positive effects observed in the cell culture experiments, the molecular
mechanism for cells interacting with peptide scaffolds is not clear, although it is possi-
ble that the presence of charged residues at every other position plays an important
role for the nonspecific interaction between the peptide scaffold and cell surface com-
ponents. To address the specific cellular response to the 3-D scaffold, a new series of
peptides was designed with incorporation of either cell adhesion ligands or short
sequences of growth factor peptides at both termini of the pure RADA peptide
(Ac(RADA)
4
CONH
2
) (Horii et al. 2007). AFM showed no obvious difference in
fiber morphology for peptide scaffolds with or without functional ligands;
however, cell culture studies on osteoblast proliferation and differentiation indicated
significantly improved preosteoblast proliferation, alkaline phosphatase activity, and
osteocalcin secretion in the designer scaffold with biofunctional ligands. Another
impressive result was discovered in an in vivo experiment using a self-assembling
peptide (RADA16-I) to achieve hemostasis on wounds made by cuts in the liver
and brain. Because hemostasis took less than 15 s, using these materials will have
a significant effect on current surgical procedures in dealing with bleeding control
(Ellis-Behnke et al. 2006).
Schneider and Pochan (2002) have described a different system of peptides with alter-
nating polar and hydrophobic residues composed of Val as an amino acid with high
b-sheet forming propensity and Lys as a modulator of pH-dependent self-assembly.
Self-assembly was designed to be triggered by intramolecular folding into a
b-hairpin structure based on the stereochemistry of central Pro residues (Fig. 14.8).
Systematic studies were carried out to understand the mechanism of molecular
self-assembly into a macroscopic hydrogel structure by a variety of biophysical
Figure 14.8 (Left) Primary sequence of peptide MAX1 with b-hairpin promoted
intramolecular folding, leading to the reversible formation of self-assembled b-sheets.
(Right) Cryo-TEM image of self-assembled peptide scaffolds. Scale bar ΒΌ 200 nm.
Reprinted from Schneider et al. (2002). Copyright 2002 American Chemical Society.
