Strategy for a Biomimetic Paradigm in Dental and Craniofacial Tissue Engineering - Biomimetics: Advancing Nanobiomaterials and Tissue Engineering - page 132

Recently, mechanisms of vascular remodeling of tissue engineered
vascular grafts have shown it to be a process largely dependent on an
infl ammatory response to the implanted construct [79]. Although seeded
bone-marrow-derived cells were no longer found 1 week after implanta-
tion, they were found to secrete high levels of MCP-1 which is a potent
monocyte chemokine resulting in a strong recruitment of monocytes to
the tissue engineered graft. The recruited host monocytes in turn secreted
cytokines, growth factors, and proteases necessary to trigger migration/
proliferation of endothelial cells which eventually led to remodeling of
the graft. Therefore, infl ammatory responses to implanted materials may
not necessarily be detrimental and together with the paracrine effects of
implanted cells may cooperate to bring about vascular remodeling.
Some authors suggest that local infl ammation initiates bone regenera-
tion by stimulating the migration of MSC, fi broblasts, endothelial and
immune cells, such as macrophages, that drive the formation of the soft
callus during fracture repair [80]. The earliest phase of fracture heal-
ing is in fact characterized by local tissue hypoxia and an infl ammatory
response. Hypoxia and hypoxia inducible factor (HIF) reestablish the dis-
turbed oxygen supply by promoting angiogenesis via increased secretion
of VEGF, IL-6, and IL-8. IL-6 and -8 are strong pro-infl ammatory factors
that are up-regulated during hypoxia and increase the migration of leu-
kocytes [80].
Moreover, a common feature in both normal bone remodeling and frac-
ture repair is the requirement for vascularization. During fracture repair
this is tightly linked to the infl ammatory phase of healing. Infl ammatory
cytokines such as IL-1 b have been shown to potentiate endothelial cell
responses increasing their proliferation and augmenting their ability to
form tube-like structures in vitro [81]. Transplanted MSC also appear to
react to the infl ammatory environment by secreting MCP-1 and GCP-2
which then lead to increased VEGF presence at the site of injury [82].
Manipulating the local infl ammatory environment by providing the
right signals may stimulate endogenous repair responses. Insight from
stem cell-based bone repair studies have shown the limited contribution
of the cells to newly formed bone, and confi rm the evolving hypothesis
that they may act principally through secreted trophic factors which are
mostly proangiogenic. When further coupled with the local infl ammatory
environment they can lead to vascular ingrowth and host progenitor cell
recruitment [83].

6.4.3 Biomimetic Model of Nature's Response to Injury?

Concurrent with this new concept is another old idea being revisited; that
of circulating progenitor cells which can be mobilized in response to injury
and contribute to the healing process. It has been shown that fracture may