# Bioengineered Skin Substitutes: Advances and Future Trends
## 2 Skin Injuries and Common Treatment Techniques  
The human skin consists of three major components including a superficial epidermis, a dermis, and a hypodermis [4]. The epidermis is composed of several layers. The outermost layer contains dead cells, which shed periodically and are continually replaced by cells derived from the basal layer [5]. The dermis connects the epidermis to the hypodermislayer, and due to the high content of collagen and elastin fibers, the dermis gives skin its strength and elasticity [6]. The hypodermis is the deepest layer of the skin located underneath the dermis. The hypodermis consists mainly of adipocytes, which accumulate fat. It also plays a role in thermoregulation, protection and provides insulation and cushioning for the integument [7].  
The integrity of skin can be disrupted by various factors, leading to different types of wounds including acute and chronic wounds. Furthermore, wounds can be further split into mechanical injuries such as those caused by external factors (abrasions and tears) and skin injuries raised from radiation, electricity, corrosive chemicals, and thermal sources causing severe burns [8].  
Skin wound healing is a complex, multi-stage process, which can be divided into homeostasis, inflammation, proliferation, and remodeling (maturation) phases [1]. To facilitate skin repair, the fine-tuned activation of numerous cell types such as keratinocytes, fibroblasts, endothelial cells, and immune cells is required. Furthermore, these cells secrete a variety of proinflammatory mediators, growth factors, and cytokines that promote skin repair [2]. Among immune cells, macrophages appear to be pivotal in this process [9; 10; 11]. They appear early during wound healing as so-called M1-polarized macrophages and differentiate to M2-phenotype at later stages of skin wound healing [12; 13]. The phenotype change from M1 to M2 seems to be crucial to support the appropriate wound healing process. In contrast, prolonged M1-macrophage persistence in the wound might results in enhanced inflammation, leading to excessive scarring and delayed wound healing [11; 14].  
The human body is capable of healing minor superficial skin injuries by epithelialization without any particular treatment. However, large and deep skin defects require skin substitution to heal properly [15].  
In particular, non-healing chronic wounds impose an immense financial burden on the healthcare systems and societies [2]. The primary reason for the impaired healing of chronic wounds is repeated tissue insults or accompanying diseases such as diabetes [16]. Moreover, in hard-to-heal chronic wounds, impaired vascularization is the main cause of delayed healing that might lead to tissue necrosis and, eventually, amputation [13; 17]. In fact, capillaries are responsible for the metabolic exchange between blood and tissues [18; 19]. If the angiogenesis process is disturbed, the wound cannot heal properly and the healing period is prolonged [18; 19]. Thus, rapid neovascularization within only days after skin substitute implantation is of vital importance for the efficient healing of those wounds [12; 13; 18; 20; 21; 22; 23].