Biomedical Engineering Reference
In-Depth Information
to secreted cellular signals participating in the tissue repair process (Ehrbar
et al
., 2008; Hubbell, 1998; Lutolf and Hubbell, 2005).
Surface functionalisation with adhesion and bioresponsive peptides
Ultimately, reproducing the ECM bioadhesive character, susceptibility to
enzymatic degradation and ability to bind growth factors will have a role in
maintaining homeostasis and, as a consequence, will contribute to control tissue
repair. The biospecific adhesion of cells to the ECM stimulates intracellular
pathways, ultimately leading to gene regulation and cell proliferation or
differentiation as well as protease secretion that modulates cell migration
(Hubbell, 2003).
Work that has been produced over the last decade by J Hubbell and
collaborators has certainly opened a new route to obtaining such an accurate
level of biomimicry. in his best known approach, Hubbell has functionalised
synthetic hydrogels with specific peptides able to confer a bioresponsive
character to the synthetic polymer during the tissue repair process. these
amino acid sequences are naturally contained in ECM structural proteins;
the relative peptides can be synthesised in a relatively easy manner by
conventional peptide synthetic methods.
in particular, synthetic hydrogels have been engineered with biomolecules
able to make them responsive to cell adhesion and migration (Lutolf
et
al
., 2003a). Poly(ethylene glycol) (PEG) hydrogels were functionalised
by a combination of integrin-binding sites and substrates for matrix
metalloproteinases (MMP). the former ensured cell adhesion, while the
latter made the hydrogel mesh controllable by the secretion of MMP, thus
facilitating cell migration. in particular, these networks contain a combination
of pendant oligopeptide ligands for cell adhesion (RGDSP) and substrates for
MMP as linkers between PEG chains. Cell culture experiments demonstrated
that proteolytic sensitivity and suitable mechanical properties were critical
for 3D cell migration inside these synthetic matrixes (Lutolf
et al
., 2003b).
these new properties were optimised by studying the enzyme kinetics of
the soluble substrate and, then, of its polymer-grafted form. The infiltration
of cells in these matrices was also proven and showed to depend on MMP
substrate activity, adhesion ligand concentration and network crosslinking
density. When these gels were loaded with recombinant human bone
morphogenetic protein-2 (BMP-2), they showed complete cell infilatration
in rat bone critical defects and the tissue was found to repair within 4 weeks.
Bone regeneration was also shown to depend on the proteolytic sensitivity
of the matrices.
in a step forward, additional biocompetent molecules were integrated in
PEG gels with the purpose of biomimicking other properties of the ECM,
such as those of retaining important growth factors and responding to cell
