Skin surface area in humans is around 1.5-2.0 m2, and the thickness is about 1.3 mm, although thickness is highly variable in different parts of the body, and thins with age. The total skin volume is about 2 L, and it has been estimated to receive about 5% of the cardiac output; total blood flow in skin would then be about 0.125 mL blood / (mL tissue * min). Wissler (2008) estimated normal cutaneous blood flow to be 0.115 mL blood / (mL tissue * min), increasing rapidly by increased skin temperature. When skin vasculature is maximally dilated, skin can receive up to ∼6-8 L blood/min, or 50-70% of cardiac output (Francisco & Minson, 2018); total blood flow in skin would then be about 3-4 mL blood / (mL tissue * min). Normal blood flow in skin is difficult to determine, because in addition to temperature, many other factors affect it, such as pressure and skin moisture.
Arterio-venous anastomoses, that can be controlled via sympathetic nervous system, are involved in the thermoregulation (cutaneous active vasodilation, CAVD). In humans, thermoregulation is achieved also by sweating and thermogenesis, mainly by shivering. Most of the skin blood flow may be nonnutritive; 85% of cutaneous microcirculation is in the thermoregulatory bed, and 15% in the nutritive capillary bed (Wollina et al., 2006). CAVD is also involved in other cardiovascular adjustments (exercise, orthostasis, etc), contributing to total peripheral resistance. Autonomic cholinergic and noradrenergic neurons innervate, region-dependently, skin arterioles, arteriovenous anastomoses, and sweat glands. Adrenergic systems maintains tonic vasoconstriction, and is activated during cold stress (Francisco & Minson, 2018). Histamine may be involved in CAVD regulation.
Skin is composed of epidermis and dermis. Below those is the hypodermis (subcutaneous tissue). Epidermis contains Merkel cells, kertinocytes, melanocytes, and Langerhans cells. New cells are formed in the innermost (basale) layer of epidermis, and maturate while moving towards the outer layer (corneum) of epidermis, filling up with keratin and losing their cytoplasm. Epidermis does not contain nerves or vasculature, but nerve endings, capillaries, and lymphatic vessels are present below it in the dermis. Epidermis and dermis are separated by basement membrane. Dermis contains also sweat, sebaceous, and apocrine glands, and hair follicles. Subcutaneous tissue (hypodermis) consists of loose connective tissue and adipose tissue; in addition to adipocytes, fibroblasts and macrophages are also abundant.
Keratinocytes contain NMDA receptors (subtype of iGluRs in glutamatergic system), participating in the regulation of tissue remodelling.
All people are too thin-skinned to allow PET studies of the skin without severe partial volume effects; skin is still often visible in PET studies, and must be avoided when defining ROIs for tissues below the skin.
The four stages of wound healing are haemostasis, inflammation, proliferation, and remodelling (Broszczak et al., 2017). Tissue injury and pain leads to vasoconstriction. Bleeding lets blood platelets to meet extravascular collagen, which activates platelets to start blood clotting and release cytokines, chemokines, and growth factors. These will attract inflammatory cells, first neutrophils, which release proteases that degrade damaged cells and extracellular matrix (ECM). Mast cells release histamine. At later phase, circulating monocytes replace the neutrophils and maturate into macrophages. Macrophages phagocytoze dead cells and ECM, but also release protease inhibitors, growth factors, and cytokines, starting the transition to proliferative phase, where keratinocytes, endothelial cells, and fibroblasts proliferate and migrate to the site of tissue damage. Fibroblasts and macrophages orchestrate the formation of new ECM and angiogenesis. Then, ECM is remodelled into scar tissue, and later to contain normal skin ECM components, with less capillaries and lower metabolic activity. Interstitial flow determines lymphatic pattern formation.
Several factors, including arterial and venous diseases, rheumatoid arthiritis, and diabetic neuropathy, can disrupt the wound healing, leading to chronic wounds and venous ulcers.
Lipodermatosclerosis is characterized by inflammatory lesions, oedema, and hyperpigmentation of the dermis of the lower limb. Skin and subcutaneous tissue is fibrotic, and veins are dilated. Tissue oxygen pressure is decreased, but oxygen tension in venous blood is high. Pericapillary “fibrin cuffs” and impaired capillary morphology have been thought to hinder the diffusion of some substrates to the tissue, although blood flow and perfusion is increased (Hopkins et al., 1983; Cheatle et al., 1990). Oxygen extraction ratio, measured using [15O]O2, is decreased in subcutaneous tissue in venous ulceration and lipodermatosclerosis (Hopkins et al., 1983; Spinks et al., 1985).
Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation and cardiovascular events (Rose et al., 2014; Teague et al., 2017). Vascular inflammation can be studied with PET using inflammation tracers.
- Extracellular matrix
- Inflammation and infection
- PET imaging of skeletal muscle
- Instructions by tracer
Hofman MS, Hicks RJ (eds.): PET/CT in Melanoma. Springer, 2017. doi: 10.1007/978-3-319-54741-1.
Wissler EH. A quantitative assessment of skin blood flow in humans. Eur J Appl Physiol. 2008; 104: 145-157. doi: 10.1007/s00421-008-0697-7.
Created at: 2017-09-26
Updated at: 2018-11-27
Written by: Vesa Oikonen