**4. Difference between traditional and scarless wound healing**

While not conclusive, studies have indicated that the mechanism of wound healing itself is different in the case of traditional wound healing and the scarless wound healing of early foetal cells (**Figure 2**). One of the primary differences being the niche and its composition itself. For instance, it has been observed that the early gestational cells modify their environmental, embryonic niche to promote regeneration during wound healing as a cell-intrinsic property [17]. However, late gestational cells are restricted to repetitive healing, in the sense that they are capable of modulating fibroblasts to increase proliferation and migration.

This is further confirmed by proteome analysis comparisons of foetal and adult fibroblasts which have revealed completely different patterns of protein expression such as the types of collagen that are more prevalent in scarless wound healing and wound healing with scar formation [11].

These findings were further supported by Siebert and his team [18], who had performed several histological and biochemical analyses on the healing of foetal wounds


#### **Figure 2.**

*Differences between scarless wound healing and traditional wound healing- representative image indicating the factors that influence traditional and scarless wound healing.*

to determine how it differs from adult wound healing to lead to a scarless wound closure, and observed that the collagen (collagen type-I) that is identical to the one found in adult wound healing sites was minimal while it was abundant in a different type of collagen (collagen type-III). Additionally, the foetal wound matrix was also rich in hyaluronic acid that had earlier been associated with decreased scar-formation during post-natal wound closure [18]. This in turn, led to the development of a theory pertaining to a hyaluronic acid/collagen/protein complex with a highly efficient matrix reorganisation potential leading wound healing in the early foetal stage debunking the theory of 'true regeneration' wherein a completely new individual is formed from a small tissue/cell.

While the quantities of collagen deposited in foetal and in adult wounds are known to be different; it has been theorised that the collagen present in foetal wounds is more for 'structural' purposes than in the form of 'scar tissue' [18]. This is further supported by the deposition of glycosaminoglycans at the wound site which promotes the migration towards, differentiation and maturation of mesenchymal stem cells (MSCs) [18, 19].

Additionally, inflammation, that is the bedrock of adult wound healing, is absent in foetal wound healing. Thus, while epithelialisation occurs in foetal wound healing, the accompanying angiogenesis that is prevalent in adult injury repairing mechanisms is absent and, as already observed by Siebert and his team, has minimal, highly organised, deposition of (the same type of) collagen and is instead dominated by the presence of hyaluronic acid [18, 20–23].

It has been speculated that altering the levels of growth factors and their inhibitors might aide in replicating the scarless wound healing mechanisms in the adult system. To that end, Bone morphogenetic protein-2, hypoxia-inducible factor 1α (HIF-1α), decorin (a TGF-β modulator), α- and β-fibroblast growth factors, IL-6, and IL-8; as well as Tenascin*,* which is a large, extracellular matrix glycoprotein synthesised by fibroblasts during embryogenesis are currently being explored by various teams. It has been theorised that Tenascin, which is present in early foetal wounds might be the factor responsible for initiating the rapid cell-migration and re-epithelialisation that is characteristic of foetal wound healing [24, 25].
