Scar Free Healing

Two important differences between embryo and adult are critical in understanding the molecular and cellular behaviour of scar-free versus scarring mechanisms of wound repair process.

First, the immune system of an embryo is not fully developed. Consequently, the repertoire of inflammatory cells, the extent of inflammatory cell differentiation and the duration of the inflammatory response in embryonic skin are all remarkably diminished compared to adult skin.

Second, the embryo is going through quick growth and differentiation, stimulated by growth factors and cytokines at levels and combinations not seen in adults.

Embryonic and adult wounds differ greatly in the levels and isoforms of cytokines and growth factors detected in the injury environment, such as transforming growth factor beta (TGF-Beta), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF).

In embryos, the cytokine and growth factor stock in the injury environment is derived from fibroblasts and keratinocytes, and thus from the natural immune response, whereas in adults it is derived from platelets and inflammatory cells which are part of the adaptive immune system.

Embryonic cells contain high levels of the TGF-Beta3 isoform, derived from keratinocytes and fibroblasts, and low levels of the TGF-Beta1 and TGF-Beta2 isoforms, derived from degranulating platelets and inflammatory cells in adult wounds. FGF is expressed at high quantities in embryos, but PDGF expression is undetected. By contrast, TGF-Beta1, TGF-Beta2 and PDGF expression is high in adult wounds, with low if any expression of TGF-Beta3 or FGF.

Investigations of wound healing in animal models have shown a possible treatment role for TGF-Beta isoforms. Injuries healing studies in rodents have shown that neutralization of TGF-Beta1 and TGF-Beta2 by antibodies greatly improves scarring. Also, wounds heal with less scarring following topical application of mannose-6-phosphate, which inhibits activation of TGF-Beta1 and of TGF-Beta2. By contrast, addition of exogenous TGF-Beta3 improves scarring in rodent models, and TGF-Beta3 deficiency in heterozygous null knockout mice results in impaired healing with scar formation.

Scar formation is the last stage in the wound healing process, and scars are not considered stable and mature until several weeks post-wounding. Nevertheless, the first 48 hours appears to be very important for the determination of the scar resolution. Best results were seen in animal models when interventions were made within this window.

A possible explanation is that the small number of master signaling molecules in the initial cytokine cascade triggered by the injury healing process can greatly affect the levels and ratios of inflammatory cells and growth factors recruited to the wound site. In addition, the recruited cells influence the receptor profiles on the target cells, further modifying the wound healing response and subsequent scar appearance.

Evolutionary relics. During our evolutionary drift injuries and wounds meant a serious danger to our body, not only due to blood loss, but also due to tissue damage or infection from foreign bodies such as dirt, splinters and bacteria. The adult wound healing process that evolved to act against this threat has 2 basic characteristics:

First, there is a quick and strong inflammatory response, with recruitment of activated macrophages, neutrophils and lymphocytes to the injured site; and

Second, there is a fibrotic "walling-off" response to isolate the foreign body, with liquefaction of adjacent tissue leading to abscess formation and scarring.

Is this response still appropriate?
"A scar is not an evolutionarily optimized end point for today's wounds," Dr. Ferguson says. "The scarring response, with its massive inflammatory overdrive, is optimized for a very different type of wound than the common sharp, clean wounds seen today. The scar is induced by this inappropriate inflammatory response."

The scars in most adults have arisen from surgical interventions. The "wounds" were done with a sharp instrument under aseptic conditions, with no contamination by strange bodies. These wounds should therefore be ideal candidates for healing, without complications, by a regenerative wound healing process rather than a scarring process.

Scars are traces of ancient, hard times. Several studies keep searching for the definitive scars solution.

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