In contrast to fetal scarless healing, adult mammals typically repair wounds with fibrosis. Recently, adult skin was shown to heal without scarring after fractional photothermolysis that creates arrays of micro-thermal wounds. How such scarless healing is achieved remains unclear. We found that micro-wound healing is characterized by a distinct process with transient and low-grade inflammation. Intravital multiphoton imaging revealed rapid micro-wound closure within one day by surrounding keratinocytes with activation of genes involved in migration and differentiation. Compared with large burn wounds that heal by rapid collagen deposition from and contraction of activated myofibroblasts, micro-wounds do not contract but, instead, repair with a highly delayed process of new collagen deposition. Surprisingly, new collagen in micro-wounds is not deposited until after 5-6 weeks post-injury when new fibroblasts re-populate the site of thermolysis. New extracellular matrix, mimicking the surrounding uninjured dermis, is slowly restored about 6 months post-injury. Our results suggest that adult skin can undergo scarless healing if myofibroblast formation is prevented, and this process occurs naturally in micro-wounds due to their rapid re-epithelialization and transient low-grade inflammation.

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