Scarless Healing

Two major differences between embryo and adult are critical in understanding the molecular and cellular environments of scar-free versus scarring mechanisms of wound healing. 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 considerably diminished compared to adult skin.

Second, the embryo is undergoing rapid growth and differentiation, stimulated by exposure to growth factors and cytokines at levels and combinations not seen in adults.

Embryonic and adult wounds differ significantly in the levels and isoforms of cytokines and growth factors detected in the wound 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 repertoire in the wound environment is derived from fibroblasts and keratinocytes, and thus from the innate immune response, whereas in adults it is derived from platelets and inflammatory cells which are part of the adaptive immune system.

Embryonic cells express 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 levels in embryos, but PDGF expression is not detected. By contrast, TGF-Beta1, TGF-Beta2 and PDGF expression is high in adult wounds, with little if any expression of TGF-Beta3 or FGF.

Studies of wound healing in animal models suggest a possible therapeutic role for TGF-Beta isoforms. Wound healing studies in rodents have shown that neutralization of TGF-Beta1 and TGF-Beta2 by antibodies markedly improves scarring. Similarly, 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 final event 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 critical in determining the scar outcome. Best results were obtained 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 wound healing process can profoundly 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 affecting the wound healing response and subsequent scar formation.

Evolutionary relics

During our evolutionary drift injuries and wounds represented a serious threat to our organism, not only due to blood loss, but also due to tissue damage or infection from the invasion of foreign bodies such as dirt, splinters and bacteria. The adult wound healing mechanism that evolved to respond to this threat has two fundamental characteristics:

First, there is a rapid and robust 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 procedures. The "wounds" were inflicted with a sharp instrument under sterile conditions, without contamination by foreign bodies. These wounds should therefore be ideal candidates for healing, without complications, by a regenerative wound healing mechanism rather than a scarring mechanism.

Next > How the above sheds light on the processes of skin repair and their promising results; and how their findings and hypothesis may explain why our natural product can both prevent scars and reduce existing keloid and hypertrophic scars.

A natural skin care product for keloid & hypertrophic scarring