211 Immune Cell Model for Burn Immune Reactions INTRODUCTION The immune response that follows burn injury is often excessive and uncontrolled, leading to secondary health complications including systemic inflammation, wound deepening, delayed healing and severe scarring [1–4]. To improve burn wound healing by modulating immune processes, the reactions underlying burn-induced inflammation and skin regeneration need to be better understood. Detailed knowledge on the specific immune cells and cytokines that are involved in the inflammatory response is, however, still limited. There is a need for appropriate human 3D models to study immune dysfunction after burn injury, avoiding the use of animal experimentation. Shortly after burn injury, pro-inflammatory neutrophils and macrophages accumulate in the wound [5–7]. These phagocytic cells are essential for removal of cell debris and pathogens from the injured site [8]. High numbers of overactive and undirected innate immune cells can, however, lead to damage to healthy tissues and hamper wound healing processes [9–11]. Next to pro-inflammatory macrophages (often called M1), there are anti-inflammatory macrophages (commonly referred to as M2) which dampen inflammatory responses and support wound healing [8,12]. Later in the inflammation phase after burn trauma, T cells migrate to the wounded area to orchestrate specific anti-pathogen responses and control ongoing inflammation to advance wound healing [13,14]. T cell effector subsets Th1 and Th17 cells play a role in the enhancement of inflammation, whereas Th2 and regulatory T cells (Tregs) are involved in the resolution of inflammation [15,16]. Achieving a proper immune balance between pro- and antiinflammatory responses is essential to establish an uncomplicated and timely transition from inflammation towards wound healing. Yet it is still unknown exactly how the immune reactions after burn injury get distorted and how this can be restored. Studies in burn patients are limited by the absence of baseline measurements, differences between individuals and injuries, and restrictions in the collection of samples [6,17]. Therefore, most knowledge on burn trauma and the immune response was previously obtained through animal experiments [6,17,18]. However, the use of experimental animals involves certain disadvantages including ethical concerns and problems in translation [19]. Although the collected information is valuable, animals do not accurately resemble the human situation due to differences in skin architecture and wound healing processes [18,20–22], making it challenging to extrapolate relevant findings to burn patients. Therefore, there is a need to find alternative approaches to perform research on burn wound healing [23]. In vitro human skin models are promising alternative experimental instruments to study aspects of skin injury, based on the behavior of keratinocytes and fibroblasts [23–25]. Currently, many of the skin models fail to capture the complex 7
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