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to three weeks in a healing cutaneous wound. This phase PDGF, TNF‑α, FGF, keratinocyte growth factor and CXCL8
overlaps with the inflammatory phase, beginning with produced by neutrophils, macrophages, endothelial
the degradation of the initial fibrin‑platelet matrix and cells and fibroblasts, maintain the proliferation and
invasion of fibroblasts and endothelial cells. Proteases migration of keratinocytes which in turn induces wound
of the serine, cysteine and MMP families are secreted re‑epithelialization. [22,64‑66] During re‑epithelialization, the
to facilitate cellular migration through the fibrin clot keratinocytes migrate beneath the provisional ECM.
and provisional matrix. [47‑50] The major events of this MMP release keratinocytes from their substratum and
phase include the influx of fibroblasts, ECM deposition, help in the migration through the matrix and promotion
formation of new blood vessels and re‑epithelialization. of re‑epithelialization. [67‑69] Wound treatment with a
broad‑spectrum metalloproteinase inhibitor significantly
Fibroblasts are the key type of cells in this phase of delays re‑epithelialization in vitro and in vivo. [70,71] Wound
healing and become the predominant cell type by three to re‑epithelialization also requires the activity of various
five days after injury. Macrophages and mast cells release proteases, including the serine protease plasmin.
growth factors, including PDGF and TGF‑b, that stimulate Re‑epithelialization is delayed in plasminogen‑deficient
[25]
fibroblast activation. The fibroblasts proliferate and mice, due to the inability of keratinocytes to degrade and
produce the matrix proteins fibronectin, hyaluronic thus migrate through the fibrin matrix and the underlying
acid, collagen and proteoglycans, all of which help to dermal tissue, whereas mice deficient in both plasminogen
construct the new ECM and a platform for keratinocyte and fibrinogen exhibit more normal healing. [72,73] After the
migration. [1,14] The provisional fibrin matrix is gradually re‑establishment of the epithelial layer, keratinocytes and
replaced by granulation tissue.
fibroblasts secrete type IV collagen to form the basement
[74]
Granulation tissue is a dense conglomeration of blood membrane. The keratinocytes undergo division and
vessels, macrophages and fibroblasts embedded within a become columnar to restore the epidermal layer and
loose matrix of fibronectin, hyaluronic acid and collagen. reform a barrier to infection and moisture loss.
Granulation tissue begins to appear in human wounds The dysregulation of the proliferative phase is believed
by about four days after injury. During granulation to underlie the pathophysiology of chronic wound and
tissue formation, new blood vessels develop from fibrotic disorders such as hypertrophic scarring and
preexisting vessels (angiogenesis). Angiogenic factors are keloids. A randomized controlled trial in patients with
secreted by fibroblasts and macrophages (e.g. VEGF, basic diabetic neuropathic foot ulcers showed topical PDGF to
FGF, angiopoietin1 and thrombospondin), keratinocytes be superior to placebo in promoting healing. VEGF gene
[75]
(e.g. CXCL8 and VEGF) and endothelial cells themselves transfer was effective in increasing vascularity in ischemic
(e.g. CXCL8 and VEGF). [51‑54] Integrin avb3 at the leading leg ulcers. Among cytokines and growth factors, the
[76]
capillary tipis a prerequisite for endothelial growth, and possible targets for promotion of wound healing include
is a promising therapeutic target for angiogenesis. TNF‑α, PDGF, FGF, VEGF, IGF‑1 and EGF. [77‑80] Understanding
[55]
Blocking these processes with angiogenesis inhibitors the signals for halting the proliferative phase will help
impairs wound healing and can be corrected with growth developing new therapeutics for acute wound healing. [51]
factors such as VEGF. Over time, the fibrin provisional
[51]
matrix is replaced with type III collagen, which in turn REMODELING PHASE
is replaced by the type I collagen during the remodeling
phase. At least twenty‑eight different types of collagen The remodeling of wound tissue occurs over a prolonged
are currently known. Most collagen types in the ECM time and may last up to 1 year. It involves ECM
[56]
[51]
are synthesized by fibroblasts, however, some types are turnover coupled with a significant decrease in cellularity.
synthesized by keratinocytes. [57]
The decline in cellularity results from the apoptosis of
Approximately four days after injury, myofibroblasts residual inflammatory cells and myofibroblasts as well as
appear in the wound. TGF‑b and CXCL8 promote the regression of the neovasculature. In humans, remodeling
[59]
[58]
differentiation of fibroblasts in the granulation tissue into is characterized by both wound contraction and collagen
myofibroblasts. [48,59,60] Myofibroblast differentiation also remodeling. The balance of collagen metabolism is in
requires an interaction with cellular fibronectin containing the part determined by the regulation of MMP activity.
[81]
extra domain‑A domain. Inhibition of either fibronectin or the The process of wound contraction is produced by wound
corresponding integrin receptors prevents TGF‑b1‑mediated myofibroblasts. While remodeling, wounds gradually
myofibroblast differentiation. [61,62] Myofibroblasts exert their become stronger with time. Wound tensile strength
contractile forces by focal adhesion contacts that link the increases rapidly from 1 to 8 weeks after wounding and
intracellular cytoskeleton to the ECM. In vitro experiments correlates with collagen cross‑linking by lysyl oxidase.
[82]
have shown higher contractile forces of keratinocytes The tensile strength of wounded skin reaches at best only
compared with fibroblasts. [63] approximately 80% that of unwounded skin, but can be
increased by synthetic MMP inhibitors. [83,84] Scar formation
Re‑epithelialization is an important process during wound is the final outcome of wound repair in children and adults.
healing that starts in the early phase of healing. Platelets
in the early wound release epidermal growth factor (EGF) New therapeutic strategies can be tried to reduce an
and TGF‑b stimulate the keratinocytes at the wound edge esthetically unacceptable scar appearance. Treatment
to proliferate and migrate to cover the wound. Cytokines with TGF‑b3 formulations and neutralizing antibodies

Plast Aesthet Res || Vol 2 || Issue 5 || Sep 15, 2015 253