Biomedical Engineering Reference
In-Depth Information
recently was the critical role of VEGF in this process recognized. After bone
injury, VEGF is up-regulated during the first days and gradually decreases
in the second week [28]. It directly signals to cells involved in bone forma-
tion such as osteoblasts, and mediates their function during bone repair [12,
161-164]. Inhibition of VEGF activity leads to decreased angiogenesis, bone
formation, and mineralization [11, 165]. VEGF furthermore interacts with
signaling pathways of various osteogenic growth factors [163]. Bone morpho-
genetic proteins (BMPs) are widely studied for their multifaceted functions
in growth and differentiation of bone. Recent studies indicate that their os-
teogenic potential may be due to synergistic actions with VEGF, and crosstalk
between osteoblasts and endothelial cells [166-168].
Polymeric VEGF delivery systems for regeneration of functional bone are
required to be mechanically competent, and may also need to appropriately
mimic spatial and temporal presentation of multiple growth factors. VEGF
supply for two weeks after the initial injury may prove therapeutically benefi-
cial [28]. However, complex and difficult fractures resulting in delayed healing
may require a more prolonged application scheme [29]. Synergistic delivery
of VEGF with osteogenic growth factors, such as BMPs, may accelerate bone
formation and improve the functionality of the regenerated bone. The ther-
apeutic benefit will likely depend on the individual doses, as well as their
ratio [169].
Polymeric Delivery Systems
Mineralized PLGA scaffolds provide systems for multiple growth factor deliv-
ery that exhibit improved mechanical properties, and offer porous, bone-like
substrates that allow for bone conduction [67, 134, 137]. They may be placed
during the surgeries frequently required for severe bone fractures. The VEGF
release kinetics from these scaffolds is retarded through the mineralization
process, and may be further controlled by the polymer composition [170]. Be-
fore implantation, these vehicles may be readily seeded with cells that either
intrinsically possess bone regenerative properties [136] or that were previ-
ously subjected to ex vivo gene therapy to express angiogenic and osteogenic
factors (e.g., VEGF and BMPs) [169]. The sustained delivery of condensed
plasmid DNA encoding for both VEGF and BMP represents an alternative
strategy to yield localized and sustained presentation of these growth fac-
tors [87]. Since such approaches rely on the presence of cells that can take up,
produce, and secrete the respective factors, simultaneous delivery of compe-
tent osteogenic precursor cells may prove beneficial [87]. Furthermore, bone
healing and VEGF signaling may be improved by utilizing RGD-modified
alginate gels [57, 59, 171], and bone formation with these materials may be
regulated by the polymer degradation rate [59]. Providing multiple growth
factors [57], and/or incorporating other cell types that can actively partici-
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