Biomedical Engineering Reference
In-Depth Information
and stimulating their synthesis of collagens I, III, and V, proteoglycans, fi bronectin,
and other ECM components (Nissen et al. 1999 ) . TGF- b1 concurrently inhibits
proteases while enhancing protease inhibitors, favoring matrix accumulation.
Re-epithelization at the wound surface and revascularization of the wound proceed
in parallel with granulation tissue formation. For example, immature keratinocytes
in skin produce MMPs and plasmin to dissociate from the basement membrane and
facilitate their migration across the open wound bed in response to chemoattrac-
tants. The migration of epithelial cells occurs independently of proliferation and
depends upon a number of factors, including growth factors, loss of contact with
adjacent cells, and guidance by active contact with ECM. Adhesive ECM proteins,
such as fi bronectin or vitronectin, bind to keratinocytes and induce them to migrate
over granulation tissue as part of wound re-epithelialization (O'Toole 2001 ) .
Subsequently, provisional matrix components, such as hyaluronic acid and fi bronec-
tin, are gradually replaced by collagen and proteoglycans.
The predominant collagen subtype in skin changes from type III (in the early
healing wound) to type I in the mature wound. Collagen is constantly being degraded
and resynthesized even in normal intact tissues. Following injury, the rate of colla-
gen synthesis increases dramatically for approximately 3 weeks. The gradual gain
in wound stiffness and tensile strength is due not only to continuing collagen depo-
sition, but also to collagen remodeling. The initially, randomly distributed collagen
fi bers become cross-linked by enzyme lysyl oxidase and aggregated into regularly
aligned fi brillar bundles, oriented along the line of stress of the healing wound. The
net increase in wound collagen is determined by the balance of its synthesis and
catabolism. The degradation of fi brillar collagen is driven by serine proteases and
MMPs under the control of the cytokine network. Production of MMPs and TIMPs
by fi broblasts is inducible and tightly regulated by cytokines, growth factors, hor-
mones, and contact with ECM components.
Collagen is also closely involved in wound contraction - inward movement of
the wound edges, which occurs as a result of an interaction between fi broblast loco-
motion and collagen reorganization. The contraction is mediated by attachment of
collagen fi brils to cell-surface receptors. The resulting contraction force generated
by cell motility brings the attached collagen fi brils closer together and eventually
compacts them. A specialized subset of fi broblasts with muscle-like contractile fea-
tures called myofi broblasts may be also involved in wound contraction (Desmouliere
et al. 2005 ). As remodeling progresses, there is a gradual reduction in the cell num-
ber and vascularity of the reparative tissue which results in the formation of a rela-
tively avascular and acellular collagen scar. Remodeling of the scar can continue for
1-2 years. The relative weakness of the scar compared to normal tissue is a conse-
quence of the collagen fi ber bundle orientation and abnormal molecular cross-linking.
For example, because the fi bers in normal tissue are relatively randomly organized
rather than the fi bers oriented parallel in scar, the maximum breaking strength of
mature scar in skin is only 70% of the intact skin. In summary, the ECM dictates and
directs wound healing to a great extent by inducing the cell stickiness, movement,
proliferation, and differentiation. The growing body of knowledge of ECM metabo-
lism in wound healing and how cells interact with it can help developing new
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