In the final phase of structural repair, the granulation tissue is remodeled into a relatively acellular fibrous scar tissue (figure 2.4). The scar differs from normal dermis in several ways (Miller and Gay, 1992; Davidson et al., 1992; Linares, 1996). Fibronectin and HA levels return to normal, but the level of decorin PG is lower than in normal skin, and the level of chondroitin-4-sulfate PG is much higher. The organization of the ECM is also different. The number of elastin fibers is reduced in scar tissue. Instead of the random basket-weave organization of normal dermis, type I collagen fibers in scar are broken down by MMPs and cross-linked by the enzyme lysyl oxidase into thick bundles oriented parallel to the surface of the wound. The MMPs appear to be produced by both the epidermis and fibroblasts of the granulation tissue. MMP synthesis by the fibroblasts appears to require an interaction with the epidermis, since synthesis is much reduced in vitro in the absence of epidermis (Grillo and Gross, 1967). Growth factors do not influence the cross-linking process itself, only the amounts of collagen available to be cross-linked (Mast, 1992). As the scar matures, the density of the vascular and neural networks in the granulation tissue returns to normal and there is a reduction in the number of fibroblasts by apoptosis (Mast, 1992; Miller and Gay, 1992; Davidson et al., 1992; Grinnell, 1994; Desmouliere et al., 1995; Lorena et al., 2002). Establishment of a mature, stable scar takes ~80 days in rodents, but at least six months in humans. Although the tensile strength of the scar tissue increases in proportion to the degree of cross-linking, it achieves no more than 70%-80% of the tensile strength of normal dermal tissue (Mast, 1992).
There must be a variety of feedback loops involving inhibitory factors that bring the repair process to an end, but these are not well understood. The factors that play a role in terminating the remodeling of granulation tissue matrix and which cells produce them remain largely to be worked out.
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