Biomedical Engineering Reference
In-Depth Information
structural integrity for subsequent tissue formation. Strategies suitable to
meet the particular needs of different applications may closely mimic normal
VEGF signaling, or be bioinspired approaches that go beyond what normally
occurs in the body. Strategies using both concepts may prove particularly
beneficial.
3.1.1
Biomimicry of ECM Sequestering Characteristics
Polymer systems that simulate normal ECM-sequestering characteristics may
enable control over VEGF temporal and spatial availability, and potentially
enhance the effectiveness of VEGF signaling. Delivery of VEGF in associa-
tion with polymeric ECM mimics may maintain the bioactivity of the growth
factor by protecting it from proteolytic degradation and stabilizing the active
conformation of the protein. This concept has been supported by the finding
that VEGF release from alginate, which exhibits macromolecular properties
similar to the natural ECM, leads to greater bioactivity of the factor than
direct administration of VEGF [30]. Similarly, VEGF conjugation to fibrin,
heparin, or hyaluronan oligosaccharides protects it from clearance, and in-
duces vessel formation more effectively as compared to VEGF alone [31-34].
Incorporation and release of VEGF from polymeric depots in which it is en-
capsulated have demonstrated maintenance of VEGF bioactivity for up to
30 days [67].
Mechanical stimulation and enzymatic matrix degradation represent typ-
ical biologic mechanisms triggering the liberation of VEGF from its ECM
depots [24, 25], and their mimicry may allow for localized VEGF supply in
concentrations that correspond to the specific cellular demands. Alginate en-
capsulated VEGF binds in a reversible fashion to the polysaccharide and its
release is regulated through mechanical stimuli (Fig. 4) [25]. Implantation
of these matrices, followed by mechanical stimulation in vivo, can enhance
blood vessel formation, indicating the efficacy and potential clinical utility of
mechanically responsive VEGF delivery systems (Fig. 4) [25]. To mimic en-
zymatically driven VEGF release from ECM stores, polymeric vehicles have
been developed that respond to the local activity of proteolytic enzymes (e.g.,
MMPs, plasmin, heparanase) provided by invading cells [32, 35]. For example,
fibrin or peptide cross-linked poly (ethylene glycol) (PEG) gels [31, 35] incor-
porate VEGF via covalent linkages, or by covalently linking heparin-binding
peptides, which then provide affinity sites for VEGF [35-38]. Cellular inva-
sion leads to VEGF release due to the action of ECM degrading proteases [38].
In addition to modifying the VEGF binding characteristics of the poly-
meric vehicle, one also may exploit the distinct ECM-binding and diffusion
characteristics of the different VEGF isoforms. Specifically, VEGF121 is not
retained by matrix proteins, and is freely diffusible [24]. Delivery of VEGF121
may allow signaling over great distances. In contrast, delivery of VEGF165,
