678 WOUND HEALING 8 



granulation tissue preclude further epithelial growth. Van den Brenk ( 1 956) believes 

 that epithelial migration ceases when the vessels of the granulating area mature and 

 the capillary loops at the advancing epidermal edge disappear, but his explanation 

 fails to account for the fact that clean granulation tissue, regardless of its age, will 

 readily accept split thickness skin grafts and the periphery of these grafts will 

 migrate outward in a normal fashion. Connective tissue growth in vitro is definitely 

 antagonistic to epithelium (Santesson, 1935; Medawar, 1937; Parshley and Simms, 

 1950), perhaps in relation to a difference in optimum pH requirements or to the 

 liberation of inhibitory factors by the fibroblasts. The possibility that epidermis 

 possesses only a limited capacity for migration in vivo cannot be ignored. If such 

 is the case, then it must be related to cessation of cell divisions at the wound edge. 

 Either the stimulus from the advancing sheet is no longer transmitted or else the 

 cells are unable to acquire sufficient energy for continued mitotic activity. A study 

 of the mitotic rate in extensive wounds, which fail to epithelialize, would be of 

 interest in this respect, however histological sections from such wounds reveal that 

 the migrating epithelium is thickened, indicating that sufficient cells are present 

 and that the failure is due to cessation of migration. 



(iv) Method of migration. The bulk of evidence regarding epidermal migration 

 has been obtained from studies on amphibia and supported by similar findings in 

 mammals. This subject has been thoroughly reviewed by Arey (1936). In amphibia 

 the epidermis consists of an outer cuticular layer overlying large glandular and 

 small epidermal cells. This relatively simple epithelium lends itself well to a study 

 of individual cell movements. Although amphibian wound healing differs in many 

 respects from mammals, the pattern of migration appears to be similar. 



Peters in 1885 observed that creation of a skin defect resulted in rapid movement 

 of adjacent epithelial cells over the area. According to Barfurth (1891) such mi- 

 gration was independent of mitosis and was, he believed, the resvilt of a combined 

 active ameboid and mass movement involving all cells of the advancing sheet. 

 His interpretation received considerable support (Klebs, 1875; Born, 1896; Oppel, 

 1 91 2; Poynter, 191 9; Arey, 1932; Herrick, 1932). On the other hand, the opinion 

 of Rand (1905) was that individual movement of constituent cells is the chief 

 means of movement of the whole sheet. Other investigators placed more stress 

 on mass movement of cells (Oppel, 191 3; Osowski, 19 14), and Oppel (191 3) 

 introduced the term "Massenbewegung" to indicate this phenomenon. Arey (1932) 

 observed the same mass movement in fish and salamanders as did Chiakulas (1952) 

 in epithelial grafts of Triturus. It was also noted by Chiakulas (1952) that when 

 grafts failed to fuse with adjacent skin, there was a piling up of epidermal cells 

 similar to that reported by Arey and Cavode (1943). Another explanation brought 

 forth by Holmes (1914) and Herrick (1932) was that peripheral cells of the 

 advancing sheet pull those which lie further behind. This view seems unreasonable 

 even though there can be no doubt that the initial stimulus for migration is 

 mediated through cells at the wound edge. Lash (1955, 1956) re-studied the 

 problem of migration in amphibia and concluded that its complexity precludes 

 use of either the term "Massenbewegung" or "individual ameboid movement." 

 He observ^ed four distinct events: a) detachment from the underlying basement 



