Scar Remodelling

Scar remodelling is the last and longest phase of repair, beginning while proliferation is still under way and continuing for a year or more. The type III collagen laid down quickly in granulation tissue is progressively replaced by type I; fibrils thicken, and lysyl oxidase forms covalent cross-links that raise tensile strength. Matrix metalloproteinases and their inhibitors control the turnover that permits this substitution, myofibroblasts expressing alpha-smooth muscle actin contract the wound and then largely undergo apoptosis, and capillary density falls, which is why a scar pales as it matures.

Strength recovery is slow and incomplete. A wound holds a few percent of intact tensile strength at one week and around twenty percent at three weeks, and the mature scar plateaus below the original tissue rather than reaching it. Regulation can fail in either direction: hypertrophic scar stays within the original wound margins and often regresses, while keloid extends beyond them and recurs after excision. Early-gestation fetal wounds heal without scar, an observation that has shaped the field for decades without yet producing a therapy.

The conceptual point is that repair is not regeneration. Scar restores continuity with a matrix of different fibril diameter, alignment and cross-link chemistry, and mechanical loading in this window influences fibre orientation more than most drugs do.

The cautionary case belongs here. Avotermin, a recombinant TGF-beta3 developed specifically to reduce scarring, produced encouraging results in early controlled human studies and then failed to meet its endpoints in phase 3, ending the programme. That is the benchmark a scar-reducing peptide claim should be measured against, and most such claims rest on rodent histology scored by an unblinded observer.