Wound contraction is the mechanism by which the edges of an open wound come together as a result of forces from within that wound. This is not the same as scar contracture, which is the shrinkage of a closed wound. However, the two are clearly related. The development of hypertrophic scars has been shown to correlate with the time a wound takes to heal (Deitch et al., 1983). If a wound takes more than 21 days to heal it will have a 78% chance of developing a hypertrophic scar prone to wound contracture. Clearly techniques which involve wound closure, rather than wound cover, will have a favourable outcome.
The reduction in the size of a surgical wound over time is also dependent on the surgical procedure used to treat that wound. An open wound will contract faster than a wound treated with a skin graft (Sawhney and Monga, 1970). The contraction of a wound covered with a skin graft depends on the percentage of the dermal component of the graft, rather than the thickness of the graft (Corps,
1969), and a skin flap will prevent contraction of a wound to a greater extent than a skin graft (Baran and Horton, 1972). One study has shown that wounds covered with full thickness skin grafts contract by 44.9%, whilst equivalent wounds covered in split thickness skin grafts contract by 69.9% (Sawhney and Monga, 1970). A wound covered with an expanded meshed split skin graft contracts more than with a sheet split skin graft (Petry and Wortham, 1986). Meshing a skin graft has no effect on the rate of wound contraction if the meshed graft is not expanded (Fifer et al., 1993).
On the cellular level, two main theories exist to explain the phenomenon of wound contraction. The first proposes that the myofibroblast is responsible for the contractile force. Myofibroblasts are cells which show morphological and biochemical features of both fibroblasts and smooth muscle cells. First demonstrated in rat granulation tissue (Majno et al., 1971), they can now be identified using monoclonal antibodies to a-smooth muscle (Skalli et al., 1986). Electron microscopy has demonstrated that they contain thick cytoplasmic fibril bundles (stress fibres) and cell to cell contacts similar to hemidesmosomes (Gabbiani et al., 1972). It is believed that these structures allow contraction and subsequent rearrangement of the surrounding connective tissue.
The second popular theory proposes that fibroblasts exert a contraction force by extending and then retracting filopodia, rather than by contraction of their entire cytoskeleton. This explains the observation that there is poor correlation between the presence of myofibroblasts and wound contraction (Darby et al., 1990). Other studies have shown that stress fibers are not always present in a contracting wound (Ehrlich, 1988). Myofibroblasts may appear after the dynamic contraction phase and have a role in maintaining tension within the tissue while the extra-cellular matrix is remodelled. In fact a-SMA expression may be associated with terminal differentiation of proliferative wound fibroblasts prior to apoptosis. Accelerated maturation of a closed wound into a mature scar has been shown to be associated with a rapid reduction in the myofibroblast population, which appears to be due to an increase in the apoptotic cell death (Desmouliere et al., 1995). The process of normal wound repair after tissue injury follows a closely regulated sequence including the
activation and the proliferation of fibroblastic cells, and their subsequent differentiation into myofibroblasts. The control of this process is probably related to the cytokine profile, the extra-cellular matrix components and cell to cell interactions. In tissue flaps the maximum number of myofibroblasts are present after 2 days (Garbin et al., 1996). This compares with the maximum number of myofibroblasts being present in granulation tissue at 10 days. This correlates with the observation that there is a decrease in the rate of contracture formation in bums scars which are released and resurfaced with free flaps (Ohmori, 1982). Similarly, myofibroblast populations have been shown to decrease much more rapidly in wounds covered with full thickness skin grafts compared to wounds covered with split skin grafts (Rudolph, 1979). This may explain the observation that full thickness skin grafts appear to reduce myofibroblast proliferation in dupytrens disease and reduce recurrence rates (Rudolph and Vande, 1991). In pathological situations, the normal resolution stages are abolished and the proliferation of myofibroblasts continues, inducing excessive accumulation of extracellular matrix. The differentiation of fibroblastic cells into myofibroblasts is an early event in the development of tissue fibrosis for many fibroproliferative disease states (Cassiman et a l, 2002;Yang and Liu, 2002;Morishima et al, 2001).
Keloids and hypertrophic scars are the dermal equivalent of these fibroproliferative disorders. TGF-P has been shown to enhance collagen fibronectin and proteoglycan synthesis by wound fibroblasts (Ignotz and Massague, 1986), as well as reducing matrix destruction by increasing collagenase inhibitors (Overall et a l, 1989). TGF-p has been identified in vivo
in a number of fibroproliferative diseases, including scleroderma (Kulozik et al., 1990), pulmonary fibrosis(Khalil et al., 1996) and glomerulonephritis (Border and Noble, 1998;Peters et al., 1997). Increased levels of TGF-p messenger RNA have been found in hypertrophic scars following thermal injury (Ghahary et al.,
1993), and fibroblasts cultured from hypertrophic scars, keloids and dupytrens nodules have all been shown to respond with enhanced collagen protein synthesis to exogenous TGF-p when compared to control wound fibroblasts (Younai et al., 1994;Badalamente et al., 1992). Bums patients with severe hypertrophic scarring have been demonstrated to have increased levels of serum TGF-p (Polo et al., 1997). It therefore seems feasible that an imbalance in the production of cytokines by immune cells may be the mechanism responsible for proliferative scar formation in bums patients. Alpha-interferon, which down regulates the effect of TGF-p on fibroblasts, has been used to treat hepatic(Serejo et al., 2001) and pulmonary fibrosis (Kamisako et al., 1993). More recently it has been used in a clinical trial on bums patients with hypertrophic scarring, with improvement in seven out of nine patients (Tredget et al., 1998).
The extracellular matrix of hypertrophic scars also contains the large proteoglycan versican which binds water and attracts it into the scar, as well as having an abnormally high type III collagen content. The small proteoglycan decorin may also be important in the formation of hypertrophic scars. Decorin has a region in its protein core which binds TGF-p and neutralizes it (Yamaguchi et al., 1990). The appearance of decorin in wounds of bums patients with hypertrophic scarring has been shown to occur 12 months after
wounding (Sayani et al., 2000). This is significant as this is the time after wounding that hypertrophic scar resolution is considered to begin.