Biomedical Engineering Reference
In-Depth Information
leads to changes in cell morphology, migration, differentiation, and survival,
and is necessary for optimal activation of growth factor receptors (e.g., VEGF
receptors) [40-42]. Consequently, integrins can act as master regulators in
VEGF signaling.
Delivery systems that promote adhesion of specific cell type(s) (e.g., cells
involved in angiogenesis, bone repair, and nerve regeneration) may be re-
quired in certain applications of VEGF, specifically those in which it is de-
sirable to mimic integrin signaling events normally occurring during tissue
repair. Traditional biomaterials, however, induce nonselective cell adhesion
via unspecific protein adsorption, and this may lead to unwanted tissue re-
sponses, such as foreign body reactions and fibrous encapsulation of the
delivery vehicle [44, 45]. In order to selectively guide cell adhesion, VEGF
may be delivered from matrices fabricated from naturally occurring ECM ma-
terials (e.g., collagen, fibrin) that inherently provide the desirable integrin
ligands [32, 33, 46]. Alternatively, ECM molecules may be used to simply coat
the surface of polymer vehicles. However, the binding mediated by secondary
forces (e.g., hydrophobic and electrostatic interactions, and hydrogen bond-
ing) is often weak, reversible, and may change the active conformation of the
proteins [44, 47]. To increase the quantity of adsorbed ECM molecules physi-
cochemical modifications of the polymer may prove useful [48-50], however,
in these approaches the ECM molecules may still be subject to denaturation.
The limitations associated with protein adsorption may effectively be over-
come by presenting cell adhesion sites in the form of small immobilized
peptides. Many ECM molecules (e.g., fibronectin and collagens) contain the
tripeptide arginine-glycine-aspartic acid (RGD) as their cell recognition mo-
tif [51, 52], and this peptide sequence may serve as a useful cue to modulate
cellular interactions with VEGF delivery systems. Presentation of RGD se-
quences on otherwise nonadhesive matrices such as alginate and PEG renders
these matrices bioactive, and may selectively guide tissue formation in re-
sponse to VEGF release [35, 53, 54]. The peptides are typically covalently
linked to the materials (e.g., between carboxyl groups present on polymers
and amino groups on the peptide) by means of bifunctional reagents. Vari-
ation of the surface density, the particular type (e.g., GRGD vs. RGD), and
the conformation (e.g., cyclic peptides vs. linear) of the utilized sequence fa-
cilitates further control over the cell responses (for detailed review see [55]).
Alginate gels, for example, have been successfully modified with RGD pep-
tides using carbodiimides chemistry [53, 56-58]. Adjustment of the peptide
density and degradation rate of the alginate chains allowed for specific control
over cellular adhesion, cell phenotype, and tissue formation, while caus-
ing minimal immune response and little capsule formation around the im-
plant [58-60].
In some cases, the polymeric systems may need to effectively prevent cellu-
lar adhesion. In particular, VEGF delivery systems in contact with blood (e.g.,
polymeric coatings of vascular stents) must prevent unspecific adhesion of
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