F.B. Niessen – On the nature of hypertrofic scars
Wound healing in susceptible individuals can result in the development of hypertrophic scar tissue, characterised by an excessive deposition of tissue collagen, water, fibronectin and proteoglycans in the extracellular matrix.12 But, despite advances in biochemical and histopathological knowledge, the exact mechanism of excessive scarring remains unknown. Probably because of the striking amount of dermal tissue in these scars, most of the literature is focused on dermal processes to elucidate the pathogenesis of hypertrophic scars. In our clinical practice, however, we have never seen the development of hypertrophic scars out of striae, in which the dermis is traumatised but the epidermal continuity is still maintained. On the contrary, when a meshed skin graft is used in burn patients, the holes within the mesh where the new epidermis will develop are especially prone to hypertrophic scar formation. Furthermore, it has been reported that deep second degree burn wounds, in which less epithelial tissue remains, are more prone to hypertrophic scar formation compared with superficial second degree burn wounds.117 This raised the question whether or not specific epidermal processes are as important in the formation of excessive scar tissue as the dermal events are.
When the skin integrity is disrupted, keratinocytes migrate over the wound bed to protect the body as soon as possible against infection and water loss, whereas the dermal tissue is patched up temporarily by granulation tissue. We surmise that if the wound is closed by this cell migration and the barrier function is complete, keratinocytes will return to a quiescent stage and will be responsible for a signal to the dermis, which slows down the dermal repair processes and provides the onset of extracellular matrix remodelling from young to mature scar tissue. In case of hypertrophic scar formation this signal seems to be lacking or is at least inadequate. The fact that completion of the reepithelialization process, at about three weeks following injury,111,118-120 correlates well with the onset of hypertrophic scar formation,12,121 and the fact that epithelial-mesenchymal interactions seem important in scarless foetal healing,122 supports this contention. We have found that hypertrophic scars are accompanied by an increased epidermal acanthosis as well as an abnormal keratinocyte proliferation and differentiation, compared with normal scars.81 In addition, cytokine expression in scar tissue show a difference between the epidermal cytokine-profiles in hypertrophic compared with normal scars. In the inframammary breast reduction scars epidermal IL-1a showed a
significantly lower, and epidermal PDGF and IL-4 a significantly higher expression in hypertrophic scars compared with normal scars, both at three and twelve months following surgery. The dermal expression on the other hand showed just a higher expression of PDGF. Even more interesting was the observation that the number of epidermal Langerhans cells was significantly increased in hypertrophic scars. Keratinocytes and Langerhans cells are known to act as an immunological signalling and protecting interface between the external environment and the organism.17 In theory, when epidermal cells sense an insufficient barrier function they remain activated, and continue to signal to the dermis, resulting in hypertrophic scar formation. A sufficient protecting interface, on the other hand, is responsible for an adequate interaction and provides the onset of remodelling young granulation tissue into mature scar.45,46,48
This thesis gives rise to a switch in paradigm, that would focus on epidermal processes in addition to dermal abnormalities in hypertrophic scar formation. This ultimately can lead to elucidation of the basic mechanisms of excessive scar formation and can open new avenues for therapy and prevention in the near future.123
The surgeon removes his gloves, the operation is done. Meanwhile the assistant closes the remaining wound with the best of his knowledge and most of his care, and the days after tomorrow he will start his immunomodulating application therapy to provide an optimal condition for the upcoming wound healing events.