245 General Discussion influence clinical courses (discussed in Chapter 2 and Chapter 3) are critical challenges in biomedicine that need to be overcome. Generalizing observations from preclinical models to patients is complicated due to differences in physiological processes between animals and humans such as signaling pathways, wound contraction and scar formation [8,105,106]. Translatability of experimental findings can for instance be improved by using humanized animal skin models, multi-omics data analysis or by making use of systems biology, machine learning and computational networks [107,108]. A point of interest in burn research is how exactly burn wound healing differs from normal wound healing (e.g. blunt trauma, excisional wounds, scratches or punctures). Burn wounds are more complex and differences might be related to more severe systemic (metabolic) responses and the release of more danger-associated molecular patterns in burns [13,109,110]. A quick return towards a normal wound healing process could speed up recovery of burn patients. Another relevant topic is the precise role of the adaptive immune system in wound healing. While the role of the innate immune system has become clearer during recent years, the contribution of cells from the adaptive immune system during wound healing is still poorly understood. This knowledge gap became especially clear when we screened for relevant articles to include in the systematic reviews (Chapter 2 and Chapter 3). Therefore, we analyzed the levels of lymphocyte subsets and associated mediators in blood and wound tissue from burn patients (Chapter 4 and Chapter 5). However, functionality and effect of adaptive immune cells on wound healing remain to be investigated. Furthermore, it is still unclear how certain burn patients develop systemic inflammatory response syndrome, while others suffer from progressive immunosuppression. The adaptive immune system proposedly plays an important role in these clinical conditions. These questions stress the strong need for more sophisticated research models, novel treatment options to restore the balance in the immune response and markers to predict clinical disease courses and complications. Modeling of burn injury and immune response To support the reduction, refinement and replacement of animal experimentation, future research should focus on alternative approaches to study the effects of burn injury [111]. Animal-free research methods include the re-analysis of existing data, patient studies and studies using simulation models. We demonstrated the use of these animal-free approaches in this thesis. The use of in vitro models for research and therapeutic testing is an important step towards animal-free drug development [112]. Here, we proposed a burn wound model with monocyte-derived macrophages or pre-activated T cells. Other immune cells such as neutrophils or specific cell subtypes (Th subsets, M1/M2 macrophages) or combinations of immune cells could also be studied in these or similar skin and wound models [113]. Moreover, another important step forward in skin tissue 8
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