The role of macrophages in human wound healing and their response to a tissue engineered dermal replacement in human chronic wounds
Examining 20 human wound bed biopsies (pilonidal sinus and venous leg ulcers), significant differences were observed between the subpopulations of wound macrophages in acute healing and chronic non-healing wounds. The results exhibit that within the acute wound there is an accumulation of early stage macrophages (mean 20.8, SD 8.6) differentiating from monocytes which become activated and contribute to the wound healing process. There being few early stage macrophages within the chronic wound (mean 10.4, SD 6.7) (p≤0.01). Chronic wounds in comparison demonstrated a significant accumulation of tissue macrophages (mean 34.0, SD 10.5) when compared to acute wounds (mean 10.9, SD 4.4) with limited wound healing (p≤0.01). The dermagraft (DG) study comprising of 53 patients, showed that applying a biologically active dressing (1-12 dressings over 12 weeks) and compression to the wound bed, exhibited complete closure (76%) or reduction in the size of the wounds at 12 weeks, compared to compression alone. Changes in the extracellular components and an array of inflammatory cells and cytokines in fifty three paired wound bed biopsies (106) with and without DG were examined at week 0 and week 6 of treatment. On histological investigation, DG exhibited an increase in the amount of collagen present and angiogenesis in the wound at week 6 of treatment. Although there were no significant changes in the lymphocyte counts in response to the application of DG, it was possible to demonstrate a significant increase in the number of stage macrophages at week 6 of treatment (p≤0.05) and a significant reduction in the tissue macrophage counts, at week 6 of treatment (p≤0.05) in patients treated with 4 pieces of DG. The levels of different cytokine expression within the wound bed at week 6 exhibited some changes but this was not significant, in response to DG treatment. This could be to the possible presence of proteinases within the chronic wound bed hydrolysing the cytokines produced by DG. From the results attained, it was able to conclude, for clinical use 4 pieces of DG at regular dosing intervals were sufficient to achieve wound contraction or closure. This dose regimen has not been taken forward for further pivotal studies. This thesis thus represents some of the first evidence in human tissue that macrophages may play role in wound healing, and in chronic wounds, a subpopulation of macrophages can be modified to stimulate these wounds towards healing.