Chapter 06: Integumentary System
Structural Architecture of the Integumentary System
The integument (skin) is the body's largest organ, accounting for approximately to of total body weight, consisting of two main functional layers:
Epidermis: The superficial, avascular layer composed of keratinized stratified squamous epithelium.
Dermis: The deeper, highly vascularized layer composed primarily of connective tissue.
Subcutaneous Layer (Hypodermis or Superficial Fascia):
Positioned deep to the dermis, it is functionally and structurally distinct and is not considered part of the integument proper.
Composed predominantly of areolar connective tissue and adipose connective tissue.
Functions in structural cushioning and mechanical protection, long-term energy storage, and thermal insulation.
Highly vascular network makes it an ideal anatomical site for subcutaneous drug injections, facilitating rapid pharmacological absorption into the bloodstream.
Anatomical features within the dermis and subcutaneous layer include:
Hair follicles, hair shafts, and associated arrector pili smooth muscle bundles.
Exocrine structures, including sebaceous (oil) glands, merocrine sweat glands, sweat gland ducts, and epidermal sweat pores.
Cutaneous vasculature featuring branching networks of dermal arteries and veins.
Somatosensory innervation comprising tactile (sensory) receptors and sensory nerve fibers.
Structural junction points where dermal papillae interlock with descending epidermal ridges to resist shearing stresses.
The Epidermis: Strata and Cellular Composition
The epidermis is a keratinized stratified squamous epithelium comprising five distinct horizontal zones (strata) in thick skin, or four strata in thin skin, arranged from deep to superficial:
Stratum Basale (Stratum Germinativum):
Consists of a single continuous layer of cuboidal to low columnar cells resting directly on the basement membrane.
Contains actively dividing stem cells that undergo continuous mitosis to replenish lost superficial keratinocytes.
Houses pigment-synthesizing melanocytes, which transfer pigment granules into adjacent keratinocytes.
Contains specialized tactile cells (Merkel cells) that interface with sensory nerve endings (tactile discs) to function as sensitive mechanoreceptors for light touch.
Stratum Spinosum:
Composed of several layers of polygonal keratinocytes characterized by centrally placed, large, oval nuclei.
Cells possess spine-like cytoplasmic processes (desmosomal attachments) that become prominent during histological preparation as cells shrink.
Displays limited mitoses in its deepest planes.
Houses epidermal dendritic cells (Langerhans cells), bone-marrow-derived immune phagocytes that initiate immune responses against microbial pathogens.
Stratum Granulosum:
Consists of to layers of flattened, spindle-shaped granular cells containing shriveled or degenerating nuclei.
Characterized by distinct basophilic keratohyalin granules and lamellar granules.
Represents the site of keratinization (hardening of cells):
As keratinocytes enter this layer, they manufacture dense fibers of the protein keratin.
Organelles and nuclei disintegrate, leading to cell death.
Lamellar granules release lipid-rich contents into the extracellular space, creating an impermeable barrier to prevent transepidermal water loss and defend against fluid influx.
Stratum Lucidum (Clear Layer):
A thin, translucent, structureless zone located immediately superficial to the stratum granulosum.
Found exclusively in thickened regions of the epidermis, specifically the palms of the hands and soles of the feet (as well as the lips).
Cells are flat, densely packed, anucleated, and filled with eleidin, an intermediate transparent protein product formed during keratin maturation.
Stratum Corneum (Horny Layer):
The outermost, cornified protective barrier, consisting of to layers of dead, flattened, nonnucleated, scale-like keratinocytes.
Enriched with densely packed fibrous keratin and bordered by extracellular hydrophobic glycolipids.
Constantly shed (desquamated) as dander and replaced by newly keratinized cells migrating from the deeper strata.
Epidermal Variations: Thick versus Thin Skin, Pigmentation, and Markings
Variations in Epidermal Thickness:
Thick Skin:
Localized strictly to high-abrasion surfaces: the palms of the hands and soles of the feet.
Contains all five epidermal strata: stratum basale, stratum spinosum, stratum granulosum, stratum lucidum, and a prominent stratum corneum.
Features abundant sweat glands, but completely lacks hair follicles and sebaceous (oil) glands.
Thin Skin:
Envelopes the vast majority of the human body.
Lacks a distinct stratum lucidum (contains four strata total).
Contains a substantially thinner stratum corneum.
Houses sweat glands, abundant hair follicles, and sebaceous glands.
Skin Color and Cutaneous Pigments:
Hemoglobin:
An oxygen-transporting protein packaged inside erythrocytes flowing through dermal capillary beds.
Assumes a bright red color when fully oxygenated, lending a healthy reddish or pinkish tint to light or unpigmented skin.
Melanin:
A family of dark pigments (black, brown, and yellowish-brown) synthesized by melanocytes in the stratum basale.
Packaged into vesicles (melanosomes) and transferred to adjacent keratinocytes, where they form a supranuclear cap over cellular DNA to shield it from ultraviolet (UV) radiation.
Cutaneous melanin quantity is governed by heredity and environmental UV exposure; all humans maintain roughly equivalent melanocyte numbers, but pigment production and dispersal vary.
Albinism: A recessive genetic disorder wherein melanocytes lack the enzyme tyrosinase and cannot produce melanin, producing white hair, pale skin, and pinkish irises.
Carotene:
A yellow-orange lipid-soluble pigment acquired dietarily from vegetables (e.g., carrots, squash).
Accumulates inside keratinocytes of the stratum corneum and within subcutaneous adipose tissue; converted into vitamin A.
Cutaneous Surface Markings:
Nevus (Mole): A localized, harmless cellular overgrowth of melanocytes; requires regular clinical monitoring for morphological changes that may signal malignant transformation.
Freckles: Flat, yellowish or brown pigmented macules resulting from localized, hyperactive melanocyte output rather than an increased cell count.
Hemangiomas: Benign vascular tumors resulting from proliferations of blood vessels that create dermal discolorations (e.g., capillary "strawberry" or cavernous hemangiomas).
Friction Ridges (Fingerprints):
Prominent dermal and epidermal contours arranged in arches, whorls, loops, and combinations.
Interlocking dermal papillae and epidermal ridges increase mechanical friction, improving grip on physical objects and enhancing tactile vibration perception.
Unique genetic and developmental patterns serve as biometric markers.
The Dermis: Organization, Neurovasculature, and Cleavage Lines
Dermal Layers:
Papillary Layer:
The superficial zone directly underlying the epidermal basement membrane, comprising areolar connective tissue.
Features finger-like projections called dermal papillae that interdigitate with down-growing epidermal ridges to secure the two layers and distribute metabolic nutrients via capillary loops.
Richly populated with sensory nerve endings and tactile receptors.
Reticular Layer:
The deeper, thicker component of the dermis extending to the subcutaneous boundary.
Composed of dense irregular connective tissue with coarse, interlacing bundles of collagen fibers and interwoven elastic fibers.
Imparts tensile strength, elasticity, and spatial support for deep cutaneous structures: hair follicle bases, sebaceous glands, sweat gland coils, arrector pili muscles, and large neurovascular plexuses.
Cleavage Lines (Langer's Lines / Tension Lines):
Linear patterns mapping the predominant orientation of parallel collagen and elastic fiber bundles within the reticular dermis.
Surgical incisional outcomes:
Incisions made parallel to cleavage lines experience minimal mechanical tension across the wound margins, are less likely to gape, and heal rapidly with minimal scarring.
Incisions made perpendicular to cleavage lines cut across elastic and collagen bundles, causing wound edges to pull apart (gape), prolonging repair and increasing scar tissue formation.
Comprehensive Physiological Functions of the Integument
Protection:
Provides a physical barrier shielding underlying tissues from mechanical trauma, harmful industrial chemicals, microbial invasion, and thermal extremes.
Melanin absorbs damaging UV radiation, protecting vulnerable nuclear DNA from mutagenic damage.
Prevention of Water Loss and Water Gain:
Epidermal keratin and intercellular lamellar lipids create a hydrophobic seal, rendering the integument water-resistant.
Prevents dangerous dehydration from systemic interstitial fluid evaporation and prevents massive water influx during aquatic immersion.
Metabolic Regulation (Vitamin Synthesis):
Epidermal keratinocytes exposed to UV radiation convert -dehydrocholesterol into cholecalciferol (vitamin ).
Vitamin is modified by the liver and subsequently converted by kidney enzymes into calcitriol (-dihydroxyvitamin ), the hormonally active form of vitamin D.
Calcitriol stimulates small intestine enterocytes to absorb dietary calcium and phosphate ions, regulating systemic mineral and bone homeostasis.
Secretion and Absorption:
Cutaneous secretion releases sweat (water, electrolytes, urea) to clear metabolic waste, and sebum to lubricate and waterproof skin and hair shafts.
Exhibiting selective permeability, the skin absorbs specific lipid-soluble compounds while excluding polar compounds.
Enables transdermal drug delivery, allowing controlled systemic administration of therapeutic compounds (e.g., nicotine, estrogen, nitroglycerin patches).
Immune Function:
Epidermal dendritic cells (Langerhans cells) phagocytose invading pathogens, process antigenic material, and migrate to lymphatic tissues to initiate adaptive immune responses.
Complementary dermal dendritic cells survey the vascular connective tissue for pathogenic intrusion.
Temperature Regulation (Thermoregulation):
Dermal Vasodilation: Capillary networks expand under hyperthermic conditions, shunting warm blood to the surface to radiate thermal energy into the surrounding air.
Dermal Vasoconstriction: Capillary networks constrict under hypothermic conditions, shunting blood toward deep visceral structures to conserve core body heat.
Evaporative Heat Loss: Merocrine sweat glands discharge watery secretions across the epidermis; the thermal energy of the skin evaporates the sweat, lowering surface and blood temperature.
Sensory Reception:
Extensively innervated by specialized tactile corpuscles, lamellated corpuscles, free nerve endings, and hair root plexuses.
Accurately detects and relays somatic sensory modalities, including light touch, deep pressure, temperature (heat and cold), shear, vibration, and tissue injury (nociception/pain).
Hair Biology and Cutaneous Glands
Hair (Pilus):
Slender, filament-like structures of dead, highly keratinized epithelial cells originating within epidermal down-growths (hair follicles) embedded in the dermis.
Three distinct developmental varieties of human hair:
Lanugo: Extremely fine, unpigmented, downy embryonic hair appearing during the third trimester of gestation; typically shed prior to or shortly after birth.
Vellus: Lightly pigmented, fine hair that constitutes the primary human hair covering the limbs and trunk.
Terminal Hair: Coarse, darkly pigmented, longer hair found on the scalp, eyebrows, and eyelashes; following pubertal surges of androgens, terminal hair replaces vellus hair in the axillary and pubic regions, and forms the facial beard in adult males.
Exocrine Glands of the Integument:
Merocrine (Eccrine) Sweat Glands:
Simple coiled tubular glands distributed across nearly the entire body (densest on palms, soles, and forehead).
Discharge clear, watery sweat ( water, plus sodium chloride, metabolic wastes) directly onto the epidermal surface via dedicated sweat ducts and pores for evaporative thermoregulation.
Apocrine Sweat Glands:
Coiled tubular glands localized primarily to the axillae, areolae, and anogenital regions.
Ducts empty viscous, protein- and lipid-rich secretions directly into adjacent hair follicles.
Inactive until puberty; secretions undergo bacterial decomposition on the skin surface, generating characteristic body odor.
Sebaceous (Oil) Glands:
Branched acinar glands that typically empty into the neck of a hair follicle.
Synthesize and discharge sebum, an oily, lipid-rich secretion that lubricates the hair shaft, softens the stratum corneum, and exerts antimicrobial effects.
Mechanisms of Glandular Secretion:
Merocrine Secretion: Secretory products are packaged into membrane-bound vesicles and released at the apical cell boundary via exocytosis without cellular destruction (e.g., merocrine sweat glands).
Apocrine Secretion: Secretory products accumulate in the apical cytoplasm of the glandular epithelial cell; the apical portion pinches off and enters the duct system, after which the cell repairs itself (e.g., apocrine sweat glands).
Holocrine Secretion: Secretory products accumulate throughout the entire cell; the cell disintegrates entirely, releasing its contents along with cellular debris into the duct, requiring replacement by basal stem cells (e.g., sebaceous glands).
Integumentary Repair, Regeneration, and Wound Healing
Four Sequential Stages of Tissue Repair:
Stage 1 (Hemostasis and Initial Inflammation):
Cut dermal blood vessels bleed into the wound margins, exposing platelets to extravascular collagen to initiate the coagulation cascade.
Blood-borne leukocytes (specifically neutrophils and monocytes) extravasate into the wound to initiate antimicrobial surveillance.
Stage 2 (Clot Formation and Wound Debridement):
A blood clot forms, knitting the severed edges together and halting internal hemorrhage.
The surface of the clot dries, forming an external scab that seals the internal milieu from infection.
Phagocytic leukocytes clean the damaged area: neutrophils destroy invading bacteria, while activated macrophages clear cellular debris and tissue fragments.
Stage 3 (Angiogenesis and Granulation Tissue Formation):
Capillaries regenerate and branch into the wound bed (angiogenesis).
Fibroblasts proliferate and synthesize vast quantities of collagen and ground substance, producing granulation tissue: a soft, pink, highly vascularized repair tissue that fills the wound.
Macrophages in the granulation tissue continue clearing clotted blood.
Stage 4 (Epithelial Regeneration and Connective Tissue Fibrosis):
Keratinocytes at the wound perimeter divide and migrate horizontally across the granulation bed beneath the drying scab.
The overlying scab detaches as epithelial regeneration restores the stratified epidermis.
Fibroblasts remodel deep collagen deposits, resulting in fibrosis (scar tissue formation), which lacks the full vascularity and elasticity of intact dermal tissue.
Categories of Wound Healing by Intention:
Healing by Primary Intention:
Occurs in clean, linear incisional wounds with closely approximated margins (e.g., surgical incisions closed with sutures, staples, or adhesive).
Marked by minimal tissue loss, minimal granulation tissue requirement, rapid epithelial resurfacing, and the formation of a fine, hairline scar.
Healing by Secondary Intention:
Occurs in open, gaping, or irregular wounds with substantial dermal and subcutaneous tissue loss (e.g., deep lacerations, decubitus ulcers, severe burns).
Wound edges cannot be brought together; defect must fill from the base upward with extensive granulation tissue.
Exhibits pronounced wound contraction mediated by myofibroblasts, prolonged healing times, higher risk of secondary infection, and large, irregular scarring.
Healing by Tertiary Intention (Delayed Primary Closure):
Indicated for infected or contaminated wounds with significant edema.
The wound is purposefully kept open to decontaminate, drain, and develop healthy granulation tissue before being surgically sutured closed at a later date, leaving a wider scar.
Clinical Pathology: Burns, Skin Cancer, and Cutaneous Aging
Pathological Classification of Thermal Burns:
First-Degree Burn:
Involves strictly the epidermal layer.
Characterized clinically by localized redness (erythema), pain, and mild edema (e.g., minor sunburn); lacks blister formation; heals in to days without scar tissue.
Second-Degree Burn:
Involves the entire epidermis and variable portions of the underlying dermis.
Characterized by severe erythema, edema, pain, and blistering (bulla formation); fluid collects at the dermoepidermal junction; typically heals in to weeks with potential for scarring.
Third-Degree Burn:
Full-thickness burn destroying the epidermis, entire dermis, and variable amounts of the subcutaneous layer.
Appears white, tan, brown, blackened, or leathery; sensory nerve endings within the wound core are destroyed, rendering the wound site painless (though surrounding second-degree areas remain painful).
Poses severe life-threatening complications, including hypovolemic shock (from massive fluid and electrolyte loss) and systemic sepsis; requires extensive debridement and skin grafting.
The Rule of Nines:
A clinical assessment tool that maps the human body surface into regions representing or multiples of of total body surface area (TBSA), used to estimate fluid resuscitation requirements:
Adult Distribution:
Head and Neck: total ( anterior, posterior).
Anterior Trunk: (chest and abdomen).
Posterior Trunk: (upper and lower back).
Right Upper Limb: ( anterior, posterior).
Left Upper Limb: ( anterior, posterior).
Perineum: .
Right Lower Limb: ( anterior, posterior).
Left Lower Limb: ( anterior, posterior).
Total Sum: .
Infant Distribution (proportions adjusted for a larger head-to-body ratio):
Head and Neck: .
Anterior Trunk: .
Posterior Trunk: .
Right Upper Limb: .
Left Upper Limb: .
Perineum: .
Right Lower Limb: .
Left Lower Limb: .
Total Sum: .
Structural Aging of the Integument:
Stem cell populations in the stratum basale decline in both count and mitotic activity, reducing the rate of epidermal replacement and prolonging healing.
Dermal collagen fiber production decreases and existing bundles coarsen; elastic fibers lose structural resilience, leading to crease lines and wrinkles.
The population of epidermal dendritic cells decreases, reducing cutaneous immune surveillance.
Cutaneous microvasculature regresses, impairing temperature regulation and nutrient delivery.
Hair follicles produce finer, less pigmented hair or shut down entirely.
Chronic UV radiation accelerates photoaging, induces elastosis, damages cellular DNA, and serves as the primary environmental driver of cutaneous malignancies.
Cutaneous Malignancies:
Skin cancer is the most common form of human cancer; fair-skinned individuals with high cumulative sun exposure are at the highest risk, and lesions occur predominantly on the head and neck.
Basal Cell Carcinoma (BCC):
The most frequent type of skin cancer ( of cases), but the least dangerous due to slow growth and low metastatic potential.
Originates directly from the stem cells of the stratum basale.
Presents as a small, shiny, pearly papule or nodule that enlarges to display a central depression and elevated, rolled border, often with visible telangiectasias.
Predominantly localized to the face; treated with surgical excision, electrodesiccation, or Mohs micrographic surgery.
Squamous Cell Carcinoma (SCC):
Arises from the keratinocytes of the stratum spinosum.
Tends to appear on sun-exposed zones, such as the scalp, ears, lower lip, and dorsum of the hand.
Early lesions appear raised, reddened, and scaly; advanced lesions ulcerate centrally, forming concave ulcers with elevated, indurated borders.
Can metastasize to regional lymph nodes if untreated; managed via early detection and complete surgical excision.
Malignant Melanoma:
The deadliest and most aggressive skin cancer due to rapid growth and high metastatic rate via lymphatic and hematogenous routes.
Derives from neoplastic melanocytes, often arising within a preexisting mole (nevus) or de novo.
Etiological risk is linked to severe blistering sunburns, particularly during childhood.
Advanced cases with metastatic dissemination carry a poor prognosis and require systemic immunotherapy, interferon therapy, targeted molecular inhibitors, chemotherapy, and radiation.
The ABCDE Rule for Melanoma Detection:
A = Asymmetry: One-half of the pigmented lesion does not match the morphology of the opposing half.
B = Border: The peripheral margin is notched, irregular, scalloped, blurred, or poorly defined.
C = Color: The pigmentation is non-uniform, featuring variable shades of tan, dark brown, and black, occasionally with focal patches of pink, red, white, or blue.
D = Diameter: The lesion measures greater than in diameter (approximately the size of a pencil eraser, or ), or is expanding rapidly.
E = Evolving: The lesion changes noticeably over time in size, shape, surface topography, or color, or develops new symptoms such as pruritus (itching), tenderness, ulceration, or spontaneous bleeding.
Questions & Discussion
Penetration of Epidermal Strata:
Question: As you trim your roses, a thorn penetrates your palm through all epidermal strata. What are the layers of the epidermis penetrated, starting from the surface of the skin?
Answer: Because the palm is thick skin, the thorn passes through all five layers in order:
Stratum corneum
Stratum lucidum
Stratum granulosum
Stratum spinosum
Stratum basale
Hemoglobin and Cutaneous Coloration:
Question: How does hemoglobin contribute to skin color?
Answer: Hemoglobin is the oxygen-binding respiratory pigment found within red blood cells inside dermal blood vessels. When saturated with oxygen, it assumes a bright scarlet red color, which shines through the translucent epidermis to give skin a healthy pinkish or reddish tint.
Physiological Function of Friction Ridges:
Question: What is the function of friction ridges?
Answer: Friction ridges are large folds and valleys of both the epidermis and dermis. They increase friction and traction between the skin and contacted surfaces (preventing slippage when grasping objects) and enhance tactile sensitivity and vibration perception.
The Rule of Nines:
Question: What is the rule of 9s and how and what is it used for?
Answer: The Rule of Nines is a clinical estimation tool that divides the body surface into anatomical sections representing (or multiples of ) of total body surface area (TBSA). It is used in acute clinical care to determine the percentage of body surface affected by partial- and full-thickness burns, which guides fluid resuscitation calculations (such as the Parkland formula) to prevent hypovolemic shock.
Cellular and Tissue Repair Stages:
Question: What are the steps of tissue repair?
Answer: Integumentary tissue repair occurs in four sequential steps:
Cut blood vessels bleed into the wound, and inflammatory leukocytes extravasate into the lesion.
A blood clot forms to restore hemostasis; the surface dries into a scab, while macrophages and neutrophils debride cellular debris and pathogens.
Blood vessels regrow (angiogenesis), and fibroblasts synthesize a collagen-rich matrix, forming vascular granulation tissue.
Keratinocytes proliferate and regenerate the stratified epidermis while underlying fibroblasts form collagenous scar tissue via fibrosis.
Cardinal Signs of Acute Inflammation:
Question: What are the cardinal signs of inflammation?
Answer: The five cardinal signs of inflammation are:
Redness (Rubor): Mediated by local vasodilation and increased blood flow.
Heat (Calor): Caused by hyperemic delivery of warm core blood.
Swelling (Tumor): Resulting from increased capillary permeability and fluid exudation into interstitial tissues.
Pain (Dolor): Caused by direct mechanical pressure from edema and chemical irritation of nociceptors by bradykinin, prostaglandins, and histamines.
Loss of Function (Functio Laesa): Functional impairment resulting from pain, swelling, and tissue disruption.
Wound Healing Intentions:
Question: Differentiate between healing by first intention and second intention.
Answer:
Healing by First (Primary) Intention: Occurs when wound edges are cleanly cut and closely approximated (e.g., surgical sutures). Requires minimal granulation tissue, heals rapidly with low infection risk, and leaves a thin, hairline scar.
Healing by Second (Secondary) Intention: Occurs in wounds with jagged, widely separated margins and substantial tissue loss. The defect must fill with extensive granulation tissue from the base upward, involves prolonged myofibroblast-mediated wound contraction, takes longer to heal, carries a higher infection risk, and results in a larger, irregular scar.
Comparison of Cutaneous Malignancies:
Question: What are the three types of skin cancer discussed, and their description?
Answer:
Basal Cell Carcinoma (BCC): Arises from stratum basale cells; most common, least aggressive, rarely metastasizes; presents as a shiny, pearly papule with a depressed center and rolled border.
Squamous Cell Carcinoma (SCC): Arises from stratum spinosum keratinocytes; appears as a raised, red, scaly lesion that can ulcerate; exhibits moderate metastatic potential.
Malignant Melanoma: Arises from transformed melanocytes (often in a preexisting mole); most lethal skin cancer due to rapid and aggressive metastasis; evaluated using the ABCDE criteria.
Granulation Tissue Dynamics:
Question: What is granulation tissue, and when does it appear during wound healing of the skin?
Answer: Granulation tissue is a soft, moist, vascular connective tissue containing newly sprouted capillary buds, proliferating fibroblasts, and active macrophages. It appears during Stage 3 of tissue repair, filling the wound cavity beneath the scab to provide structural scaffolding for migrating epithelial cells.
Vitamin D Synthesis Pathway:
Question: How does the skin produce vitamin D?
Answer: Keratinocytes within the stratum basale and stratum spinosum contain the precursor molecule -dehydrocholesterol. Exposure to solar ultraviolet B (UVB) radiation converts this compound into cholecalciferol (vitamin ). Vitamin is transported through the bloodstream to the liver to be hydroxylated, and then to the kidneys where it is converted into calcitriol (-dihydroxyvitamin ), which stimulates intestinal absorption of calcium and phosphate.
Cutaneous Permeability:
Question: Is the skin entirely waterproof? Explain.
Answer: The skin is water-resistant, not completely waterproof. Keratin within the stratum corneum and hydrophobic lipids secreted by lamellar granules in the stratum granulosum prevent water loss from the body and limit water absorption from the environment. However, slight transepidermal water loss occurs continuously as insensible perspiration ( per day), and lipid-soluble chemicals, organic solvents, and certain drugs can penetrate the epidermal barrier.
Dissipation of Excess Heat:
Question: What are some ways the skin can dissipate excess heat?
Answer: The skin dissipates excess thermal energy through two primary mechanisms:
Dermal Vasodilation: Dermal blood vessels dilate, increasing surface blood flow to radiate heat away from the body.
Evaporative Sweating: Merocrine sweat glands discharge water onto the epidermal surface; as the sweat absorbs heat and evaporates, it cools the skin and circulating dermal blood.