68o WOUND HEALING 8 



mitosis in the epithelial sheet is related to cessation of cell movement while Howes 

 (1943) relates it to thickening of the migrating epithelium. It is interesting to note 

 that mitotic activity in cultured skin parallels the findings of m vivo wound healing. 

 Hsu (1952) observed that mitoses were extremely rare in the out-wandering 

 epithelium and Washburn (1954) demonstrated that cell division was almost 

 exclusively limited to the edge of the explant. 



A relationship exists between cell division in old and new epithelium; it de- 

 creases in the former as it increases in the latter. Large wounds have a greater 

 mitotic activity than small ones, and there is a sharp decline after epithelialization 

 is completed. Blumenfeld (1943) demonstrated that at seven days the mitotic rate 

 of the wound edge was twice as high as that of normal skin, and that the diurnal 

 periodicity common to all species, including humans, was preserved (Cooper, 1939). 



The energy source for mitosis of epidermal cells has been the subject of con- 

 siderable investigation. It is now evident that there is a difference between the 

 energy requirement for maintenance and for either migration or mitosis. Epithe- 

 lium is unable to store large quantities of energy and the amount produced is 

 sufficient for only one process or the other (Hartwell, 1955; Bullough, 1946). 



The energy necessary for maintenance appears to be relatively small. Medawar 

 (1947) demonstrated that pieces of skin can survive for at least one week in vitro 

 without any oxygen source. Under such conditions mitosis is arrested, but when 

 oxygen is again introduced, it will recur (Bvillough and Johnson, 1951a, 1951b). 

 The energy supply appears to be mediated throvigh the Krebs cycle (Bullough, 

 1952), and substrates such as glycogen, glucose, lactate, or pyruvate are all able 

 to yield sufficient quantities for mitosis. In their absence cell division is inhibited 

 both in vivo (Bullough, 1949a, 1949b) and in vitro (Bullough, 1950a, b; Bullough 

 and Johnson, ig5ib). Intermediates of the Krebs cycle such as fumarate or citrate 

 which are known to increase the rate of energy production also have a positive 

 effect, when svich substances are added in the presence of an adequate amount 

 of glucose and oxygen there is a 25-30% increase in mitotic rate. Since cell division 

 requires maximum energy production, any substance which interferes with 

 glycolysis or the Krebs cycle, e.g. iodoacetate, will result in a reduced mitotic rate 

 and ultimately cell death (Medawar, 1947). 



The critical energy level must be reached in the antephase, the period immedi- 

 ately prior to prophase. Once a cell has started to divide, it appears to be inde- 

 pendent of its environment. Mitosis goes to completion despite the presence of 

 inhibitors of glycolyses, lack of glucose, oxygen, or even death of the animal 

 (Bullough and Johnson, 1951a, b). These facts indicate that energy storage occurs 

 during antephase and that the amount stored is sufficient to meet cell demands 

 throughout mitosis. Substances which interfere with the Krebs cycle have no 

 effect once this energy requirement is fulfilled. Little is known concerning the 

 stored energy source; presumably it is creatine phosphate and adenosine triphos- 

 phate or similar compounds with a high energy phosphate bond. 



(d) Cessation of cell movement and reattachment 



Little emphasis has been placed on the events leading to cessation of migration 

 (Young et al., 1941) and reattachment. When opposing epithelial surfaces contact 



