Mutilaciones de ganadoMutilaciones de ganado
19 REBIRTHING: REBIRTHING: EL EL OJO OJO IZQUIERDO IZQUIERDO DE DE HORUS HORUS
1.4.1 Structure of the dermis
The dermis is thicker and considerably less cellular than the epidermis; its key functions include cushioning underlying organs from mechanical injury and providing nutrients to the epidermis and its appendages. The main structural component of the dermis is the extracellular matrix (ECM): a network of fibres – predominantly collagen but also containing elastin – embedded in a gel-like matrix of polysaccharides. Collagen fibres, which constitute approximately 30% of the dermal volume in mice, strengthen the ECM by forming an organised structure cross-linked by covalent bonds; the coiled structure of elastin, which represents 1% of dermal volume, provides a degree of skin elasticity [122]. Whilst the ECM is key for dermal structure, it is not simply an inert scaffolding: the behaviour of its resident cells can be regulated by ECM components, either by acting as a reservoir for biochemical signalling molecules, or through fibre-facilitated contact guidance. Additionally, the aqueous phase of the polysaccharide gel allows nutrients, metabolites and hormones to diffuse between blood and tissue cells [122].
In healthy skin the ECM is primarily populated by fibroblasts, which are responsible for secreting dermal constituents such as collagen and can produce contractile forces during healing; fibroblasts are most commonly found in close proximity to collagen fibres [123]. Mast cells and macrophages are also found in dermal tissue, and lymphocytes are present in small numbers [124, 125].
Additionally, dermal tissue contains follicles and glands, including sebaceous glands, sweat glands and hair follicles, which are in fact epidermal structures that protrude into the
temperature and vibrations, and transmitting signals to the central nervous system via a large number of cutaneous nerves.
When damage occurs to the dermis, a complex, multistep healing process is initiated. The stages of dermal healing are briefly outlined in the following sections, with additional details provided in Section 5.1.
1.4.2 Haemostasis
Cutaneous trauma routinely results in damage to dermal blood vessels, due to the abundance of capillaries found in the skin. To prevent excessive blood loss, vessels rapidly constrict and platelets aggregate to form a blood clot, composed of proteins including fibrin, fibronectin, vitronectin, trombospondin and cells such as erythrocytes and platelets [126, 127]. This clot acts to inhibit bleeding, protect underlying tissue and attract immune cells towards the wound [128].
1.4.3 Dermal inflammation
After clot formation, the release of histamine causes blood vessels close to the wound to dilate and become more permeable, which facilitates delivery of immune cells through rapid changes to blood flow around the wound site [129]. The expression of inflammatory chemokines on the lumen of the blood vessel, localised chemokine production as a result of cytokine production, and localised prostaglandin and leukotriene production leads to spe- cific immune cell recruitment to the wound site. This process is additionally modulated through production of PDGF and TGF-β1 in the clot. Once at the wound site, immune cells initially defend against pathogens: neutrophils remove foreign particles and bacteria from the site, macrophages later clear senescent cells and other wound eschar, phagocytose pathogens and present antigens to T-cells [130]. Macrophages involved in clearance undergo apoptosis, and those that remain in the wound space take on other regulatory roles during the tissue repair phase of healing [131]. The length of the inflammatory phase depends predominantly on the level of infection or presence of foreign bodies in the wound, but may be extended by immune complications [132].
1.4.4 Dermal collagen deposition
Dermal volume is initially increased by the production of granulation tissue: between 3 and 5 days post wounding (dpw), fibroblasts and myofibroblasts begin to produce new ECM components which are necessary to support further cell infiltration and angiogenesis [133]. In particular, collagen is laid down as the main structural component of the nascent ECM, along with fibrin and glycoproteins that enable cell adhesion [134, 135]. Specific details of this process are described in Section 5.1.
1.4.5 Angiogenesis
As granulation tissue and the basement membrane in the wound space begin to degrade, endothelial cells migrate into the wound space. They are attracted by growth factors – including TGF-β, FGF, vascular endothelial growth factor (VEGF) and angiopoietins – that are produced by immune cells and fibroblasts [136]. VEGF also stimulates endothelial cell proliferation, further increasing the pool of cells available to enable angiogenic sprouting of dermal capillaries, thus vascularising the wound bed [137].
1.4.6 Contraction
Wound contraction acts to reduce the size of an injury without the need to synthesise new skin components; as described in Section 1.2.2, this occurs to a greater extent in rodent skin than in humans and pigs. The primary cell types implicated in dermal contraction are fibroblasts and myofibroblasts, which differentiate from fibroblasts in response to the presence of growth factors (such as TGF-β1) and mechanical forces generated by the ECM as, for example, it resists initial wound edge retraction [138, 139, 140]. Myofibroblasts take on phenotypic characteristics of smooth muscle cells to facilitate force generation; application of these forces to the collagen and elastin fibres with which myofibroblasts have contact results in contraction of the ECM [141]. Recently, it has been shown that both myofibroblasts and fibroblasts contribute to ECM contraction, with myofibroblast-deficient wounds still exhibiting contraction [142].
1.4.7 Resolution of tissue inflammation and remodelling
Tissue remodelling is by far the longest phase of dermal healing, lasting from months to years [143]. The rate of cell proliferation in the wound space decreases, regulated by macrophage- derived growth factors, and endothelial cells, macrophages and myofibroblasts apoptose or exit the wound site [144]. This causes a reduction in the rate of production of ECM components, and helps to promote remodelling: a process through which existing collagen is either degraded or restructured into larger, more organised bundles, restoring dermal tissue to an architecture closer to that of unwounded skin [143].