Fibroblast Sheets Enable Epithelialization of Wounds That Do Not Support Keratinocyte Migration

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Abstract
Keratinocyte migration over the wound bed is the single most important parameter for wound epithelialization. Therefore, improvement of the wound bed matrix holds considerable promise for the shortening of hospitalization time in patients with ulcers, burns, and chronic wounds. We investigated wound epithelialization in athymic mice in the presence or absence of a sheet of cultured human fibroblasts. The physiology of keratinocyte growth on fibroblast sheets was investigated in tissue culture using histology, immunofluorescence, and electron microscopy. Keratinocytes from human skin explants were unable to attach or migrate on full-thickness dorsal wounds of athymic mice. Placement of a fibroblast-seeded polyglactin mesh on the wounds resulted in dramatically increased keratinocyte outgrowth. Similarly, human keratinocytes showed good outgrowth on fibroblast sheets at the air/liquid interface in tissue culture. Outgrowth was correlated inversely with fibroblast viability, indicating that the observed effect was due to the complex extracellular matrix secreted by the fibroblasts and matrix-bound growth factors rather than ongoing growth factor release. Collagen IV, a promoter of keratinocyte migration, was found to be abundant in the fibroblast-derived matrix. This study demonstrates that wounds which are unable to support keratinocyte migration can undergo epithelialization if a conducive substrate, supplying appropriate extracellular matrix and/or matrix-bound growth factors, is applied.