nents such as collagen, fibronectin, proteoglycans, and laminin [52].

Collagen composition of the wound appears to follow a similar pattern as embryogenesis. Granulation tissue is comprised of a large amount of collagen III, which is gradually replaced by collagen I. Collagen I provides a higher degree of tensile strength to the developing scar, although the final tensile strength approaches only 70% of uninjured skin [53]. A morphological change in fibroblasts ensues during wound contraction, in which fibroblasts begin to express alpha-smooth muscle actin and adapt functions of smooth muscle cells. The resulting cell is termed a myofibroblast and serves to enhance wound contraction [5].

Fetal wound healing

Fetal wound healing is typified by scarless healing and a paucity of inflammation. Epithelialization occurs more quickly with less neovascularization, and wounds heal faster than adult counterparts. Reticular collagen III is the predominant type of collagen in healed fetal wounds, in contrast to fibrilar collagen I in adult scars. Fetal skin wounds are also able to regenerate appendages such as hair follicles, sweat glands, and sebaceous glands. The transition from scarless to scarring repair appears to occur near the end of the second trimester, with the propensity for wound scarring increasing through neonatal to adult life [5].

Much of the research on fetal wound healing has focused on fibroblasts. Fetal fibroblasts exhibit different collagen expression profiles than adult fibroblasts (type III dominant), and produce comparatively more collagen in culture. Collagen expression falls to adult levels after 20 weeks gestation, concurrent with a sharp increase in MMP-1, MMP-3, and MMP-9 expression [54]. While fibroblasts appear to exhibit more vigorous activity in fetal wounds, minimal quantities of the potent fibroblast stimulant TGFhave been noted. The hyaluronan-rich amniotic fluid environment may also provide a permissive milieu for fibroblast migration and proliferation [55]. Attempts to recapitulate the secrets of fetal wound healing in adults are ongoing, though the underlying mechanisms remain incompletely understood.

Stem cells

In addition to resident epidermal stem cells in the skin, bone marrow-derived stem cells may contribute substantially to cutaneous wound healing. Bone marrow contains both hematopoietic (CD34+) and nonhematopoietic (mesenchymal) stem cells, which aid wound healing by direct contribution of cells as well as by paracrine signaling. A notable study, in which green fluorescent protein-labeled bone marrow stem cells were used to reconstitute the marrow of mice with cutaneous wounds, indicated that non-hemat- opoietic mesenchymal stem cells may contribute up to 15–20% of dermal fibroblasts in normal skin and healing cutaneous wounds [56]. Cells with a keratinocyte phenotype have also been traced to bone marrow origin [56, 57]. Evidence also exists that bone marrowderived stem cells are involved in hair follicle regeneration [58]. Bone marrow stem cells expanded ex vivo have been shown to promote neovascularization [59], appendage regeneration [60], and accelerate wound closure [61].

Endothelial progenitor cells (EPCs) are derived from CD34+ hematopoietic stem cells in the bone marrow and contribute some proportion of endothelial cells to adult skin. Transplantation of EPCs enhances wound healing in mice [62], as does topical application of EPCs to ischemic ulcers in diabetic mice [63]. Interestingly, the mechanism is thought to involve paracrine signaling from EPCs instead of direct contribution of endothelial cells [62].

Fibrocytes are a newly-identified subpopulation of leukocytes that also arise in the bone marrow, which were originally identified by their rapid recruitment from peripheral blood to wound sites in mice [64]. Fibrocytes are significantly increased in the blood of burned patients in comparison to normal individuals, and appear to localize in the deeper papillary dermis[65]. The evidence to date points towards a prominent role for fibrocytes in the fibrosis associated with hypertrophic scarring [66]. These cells may also contribute to the myofibroblast population in wounds [67].