Connective Tissue Formation in Wound Healing - E-thesis

extracellular matrix. The provisional extracellular matrix is gradually replaced by a
collagenous matrix, perhaps as a result of the action of TGF-β1 (38).
Once an abundant collagen matrix has been deposited in the wound, fibroblasts stop producing
collagen and the fibroblast-rich granulation tissue is replaced by a relatively acellular scar.
Cells in the wound undergo apoptosis (39) triggered by unknown signals. Dysregulation of
these processes occurs in fibrotic disorders such as keloid formation, morphea, and
scleroderma (2).
Matrix Remodeling
Extracellular matrix remodeling, cell maturation, and cell apoptosis create the third phase of
wound repair, which overlaps with tissue formation. Once the wound is filled with granulation
tissue and covered with a neoepidermis, fibroblasts transform into myofibroblasts, which
contract the wound, and epidermal cell differentiate to reestablish the permeability barriers.
Endothelial cells appear to be the first cell type to undergo apoptosis, followed by the
myofibroblasts, leading gradually to a rather acellular scar (7). During the proliferation phase
of wound healing (Fig. 1), fibroblasts assume a myofibroblast phenotype characterized by large
bundles of actin-containing microfilaments disposed along the cytoplasmic face of the plasma
membrane of the cells and by cell-cell and cell-matrix linkages (38, 40). The appearance of the
myofibroblasts corresponds to the commencement of connective-tissue compaction and the
contraction of the wound. The contraction probably requires stimulation by TGF-β1 or TGF-β2
and PDGF, attachment of fibroblasts to the collagen matrix through integrin receptors, and
cross-links between individual bundles of collagen (41-44). The overall collagen content of
the wound diminishes, while tensile strength increases as a result of structural modification of
the newly deposited collagen, such that unorganised collagen fibrils mature into compact
fibres. The increase in fibre diameter is associated within an increase in wound tensile strength.
Crosslinking of collagen fibrils is largely responsible for these morphologic changes and
increase in wound strength (45). The degradation of collagen in the wound is controlled by
several proteolytic enzymes termed matrix metalloproteinases, which are secreted by
macrophages, epidermal cells, and endothelial cells, as well as fibroblasts (36). In the various
phases of wound repair, distinct combinations of matrix metalloproteinases and tissue
inhibitors of metalloproteinases are needed (46).
During the granulation tissue formation wounds gain only about 20 percent of their final
strength (47). During this time fibrillar collagen has accumulated relatively rapidly and has been
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