Biomedical Engineering Reference
In-Depth Information
Wound healing response is initiated at the moment of injury with the hemorrhage
and formation of the blood clot. Immediately after that infl ammation phase is trig-
gered, which is characterized by prominent immune response involving neutrophils,
macrophages, lymphocytes, and other immune elements. In the following prolifer-
ating phase, fi broblasts migrate into the area of wound to form the granulation tissue
and to produce ECM, which is dynamically remodeled for effective wound closure
and scar development. Simultaneously, wound contraction and re-epithelization
take place. All these events are strictly regulated by wound microenvironment,
including growth factors, cytokines, and newly created ECM components. The fi nal
product of the healing process is a scar - relatively avascular and acellular mass of
collagen serving to restore tissue continuity, strength, and function. This pivotal role
of ECM in wound healing sequences can be observed throughout all stages of the
repair process.
Exposure of blood to collagen in the wound defects results in platelet activation
and coagulation cascade initiation, while the fi nal fi brin network clot serves to stop
bleeding and to plug the wound site. A number of growth factors and cytokines are
released from platelets, which play important role in recruitment of infl ammatory
cells, stimulation of fi broblasts, and evolution of granulation tissue. For example,
platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-b 1
regulate many matrix proteins including collagen, proteoglycans, fi bronectin, and
matrix degrading proteases and their inhibitors. Latent TGF-b 1, released from plate-
lets and infl ammatory cells, is activated by proteolytic and non-proteolytic mecha-
nisms to infl uence wound healing from initial clot formation to the fi nal stage of
matrix deposition and remodeling (Wahl 1999 ). ECM also acts as a reservoir for
growth factors required during healing. Fibroblast growth factors (FGF-1 and -2)
are weakly soluble with a strong affi nity for heparan sulfate. Pre-existing FGF-2
bound in the wounded ECM appears to stimulate angiogenesis and fi broblast func-
tion modulation (Mustoe et al. 1991 ). Hyaluronic acid, highly hydrated ECM com-
ponent conferring viscosity to tissues, promotes early infl ammation by enhancing
leukocyte infi ltration. It also moderates the infl ammatory response as healing pro-
gresses towards granulation tissue formation and facilitates fi broblast migration.
The neutrophils are activated during chemotaxis and produce elastase and collage-
nase to facilitate their migration. Once in the tissue, the infl ammatory cells and
fi broblasts stimulate the production of MMP-1, -2, -3, and -9 to degrade the dam-
aged ECM in preparation for macrophage phagocytosis of the ECM debris (Mott
and Werb 2004 ) . After infl ammation, the proliferative phase follows, which is char-
acterized by granulation tissue formation. It consists of cellular elements (fi bro-
blasts and infl ammatory cells), along with new capillaries embedded in a loose
ECM of collagen, fi bronectin, and hyaluronan. Fibroblasts respond to cytokines/
growth factors by proliferating and synthesizing provisional fi ber network rich in
fi bronectin. It serves not only as a substratum for migration and in-growth of cells,
but also as a template of collagen deposition by fi broblasts. There are also signifi -
cant quantities of hyaluronic acid and large-molecular-weight proteoglycans pres-
ent, which contribute to the gel-like consistency of the ECM and aid cellular
infi ltration. TGF-b1 further contributes to this fi brotic process by recruiting fi broblasts
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