Skin surface area in humans is around 1.5-2.0 m2, and the thickness is about 1.2-1.3 mm, although thickness is highly variable in different parts of the body, and thins with age. The total skin volume is about 2-3.5 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). This is utilized by warming hand to obtain arterialized venous blood to avoid arterial blood sampling. Thermal hyperaemia is impaired in diabetes (Cracowski et al., 2006). 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. 133Xe clearance technique is a reliable method for assessing skin blood flow.
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 and partly by brown adipose tissue. 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 can store ∼0.6 L of blood, mainly in the venules. In contrast to other organs, acute hypoxia induces vasoconstriction in the skin vasculature.
Skin is composed of epidermis (30-150 µm) and dermis (1-2 mm). Below those is the hypodermis (subcutis, subcutaneous tissue, 0.1 to several cm). Blood vessels in all these layers are extensively anastomosed between themselves. Vascular density is especially high in extremities and in the head. Epidermis contains Merkel cells, keratinocytes (95%), 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. Merkel cells are neuroendocrine cells, responsible of the touch sensory function. Langerhans cells are dendritic cells involved in immune response. 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. As dermal vasculature does not penetrate the basement membrane, transcutaneous absorption of O2 from the air is the major source of oxygen for the epidermis. Nutritive capillary loops and venules are located mainly just under the basement membrane. Lower in dermis and at the dermal-hypodermis junction two horizontal plexus layers provide high (non-nutritive) blood flow at demand. Lower dermis contains also numerous lymphatic capillaries. Dermis of fingertips and toes contains especially numerous arteriovenous anastomoses. Dermis contains also sweat, sebaceous, and apocrine glands, and hair follicles. Dermis has high collagen content. Below that, hypodermis (subcutaneous tissue) consists of loose connective tissue and adipose tissue; in addition to adipocytes, fibroblasts and macrophages are also abundant. The looseness of subcutaneous tissue allows the skin to move laterally and slide over joints
Blood vessels in the skin are considered to have continuous endothelial walls, but capillary fenestrations are numerous at least in fingers (Takada & Hattori, 1972). Characteristics of dermal capillaries in early literature may be artefacts caused by skin fixation procedures before microscopy (Imayama & Urabe, 1986).
Keratinocytes contain NMDA receptors (subtype of iGluRs in glutamatergic system), participating in the regulation of tissue remodelling. Keratinocytes express NK1 and NK2 receptors, and substance P regulates the production of proinflammatory cytokines.
All people are too thin-skinned to allow PET studies of the skin without severe partial volume effects. [15O]H2O assessment of calf skin perfusion in normal temperature was 0.007±0.003 mL blood / (g tissue * min), using ECAT EXACT HR+ PET scanner (Heinonen et al., 2011), which is only ∼⅒ of the estimate given above. Yet, local heating increased the perfusion to 0.055±0.015 mL blood / (g tissue * min), and whole body heat stress to 0.040±0.015 mL blood / (g tissue * min) (Heinonen et al., 2011), suggesting that changes in skin physiology could be assessed using PET. While PET studies of skin are difficult, skin is still often visible in PET studies, and must be avoided when defining ROIs for tissues below the skin. Ultrasound, confocal microscopy, optical coherence tomography, and MRI can reach the resolution required for skin studies. Systemic vascular diseases and endothelial dysfunction are often studied using cutaneous microcirculation as a model (Holowatz et al., 2008).
Many drugs can administered via the skin. Topical drug products are intended to affect the skin, and transdermal products are intended for systemic distribution. Unintended absorption of substances from cosmetic skin products can be investigated with isotope techniques; for instance 26Al can be used to measure the dermal absorption of aluminum from antiperspirant formulations (de Ligt et al., 2018).
The four stages of wound healing are haemostasis, inflammation, proliferation, and remodelling (Broszczak et al., 2017). Tissue injury and pain leads to vasoconstriction. Normally the endothelial cells prevent blood platelets from contacting extracellular matrix and intracellular collagens. 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 arthritis, and diabetic neuropathy, can disrupt the wound healing, leading to chronic wounds and venous ulcers.
Pressure with or without shear can lead to pressure ulcers (PUs) in skin and underlying tissue, especially close to bony prominences. Mechanical deformation of cells and hypoxia are probable causes of pressure ulcers. Support surfaces can affect the development of PUs in patients that are in chronic bedrest or consistently use a wheelchair. [15O]H2O PET has been used to assess blood flow in skin, subcutaneous tissue, and muscle when subjects are lying down on different support surfaces (Soppi et al., 2021).
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.
Melanin pigments are paramagnetic, and therefore high-resolution MRI can be used to detect and measure the volume of melanomas. Melanotransferrin is expressed on melanocytes and used in diagnosis of melanoma.
Keratinocytic skin tumours account for most of the skin malignancies, and include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC is the most common, and it grows slowly and hardly ever metastasises.
- Extracellular matrix
- Inflammation imaging
- PET imaging of skeletal muscle
- Adipose tissue
- Instructions by tracer
Braverman IM. The cutaneous microcirculation: ultrastructure and microanatomical organization. Microcirculation 1997; 4(3): 329-340. doi: 10.3109/10739689709146797.
Hofman MS, Hicks RJ (eds.): PET/CT in Melanoma. Springer, 2017. doi: 10.1007/978-3-319-54741-1.
Humbert P, Fanian F, Maibach HI, Agache P (eds): Agache's Measuring the Skin - Non-invasive Investigations, Physiology, Normal Constants, 2nd ed, Springer, 2017. doi: 10.1007/978-3-319-32383-1.
Ono S, Egawa G, Kabashima K. Regulation of blood vascular permeability in the skin. Inflamm Regen. 2017; 37:11. doi: 10.1186/s41232-017-0042-9.
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.
Tags: Thermoregulation, Perfusion, Wound healing
Updated at: 2022-01-26
Created at: 2017-09-26
Written by: Vesa Oikonen