261 English Summary PART 3: IN VITRO MODELING There is a growing demand for more appropriate, animal-free approaches in preclinical research due to both ethical and scientific concerns around animal experimentation. Organotypic skin models are promising alternatives for animals and are standardized, controllable, and easy to customize. To develop a model wherein burn injury and specific immune reactions could be studied, full skin equivalent models (FSEs) were generated using various clinically applied dermal matrices (Chapter 6). Using immunohistochemistry techniques and cytokine assays, the epidermal and dermal development and cell proliferation and inflammatory response were assessed. FSEs based on MatriDerm displayed many similarities to ex vivo human skin and showed re-epithelization after a burn injury was applied. In Chapter 7, we simulated innate and adaptive immune reactions by incorporating monocytes or T cells into the MatriDerm-based FSE. In the FSE, monocytes differentiated into macrophages and burn injury seemed to increase the percentage of HLA-DR+ (M1-like) macrophages. The inclusion of monocytes further increased inflammatory cytokines such as IL-1β, IL-6 and IL-8. T cells that actively migrated into the FSE showed enhanced expression of Treg and Th1/Th17 markers, irrespective of burn injury. The inclusion of T cells in the model upregulated the production of inflammatory cytokines such as IFN-γ, IL-10, IL-17A and IP-10, demonstrating the interplay between T cells and skin cells. These immunocompetent models enable the study of skin development, wound healing and specific immune reactions using a uniform dermal component. They will facilitate the testing of novel therapeutic approaches that may treat burn injuries more effectively. 9
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