Wound healing - AbsoluteAstronomy.com

Hand abrasion

Approximate days since injury
0	2	17	30

Wound healing, or cicatrisation, is an intricate process in which the skin (or another organ-tissue) repairs itself after injury. In normal skin, the epidermis (outermost layer) and dermis

Dermis

The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...

(inner or deeper layer) exists in a steady-state equilibrium, forming a protective barrier against the external environment. Once the protective barrier is broken, the normal (physiologic) process of wound healing is immediately set in motion. The classic model of wound healing is divided into three or four sequential, yet overlapping, phases: (1) hemostasis

Hemostasis

Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...

(not considered a phase by some authors), (2) inflammatory, (3) proliferative and (4) remodeling. Upon injury to the skin, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage. Within minutes post-injury, platelets (thrombocytes) aggregate at the injury site to form a fibrin

Fibrin

Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

clot. This clot acts to control active bleeding

Bleeding

Bleeding, technically known as hemorrhaging or haemorrhaging is the loss of blood or blood escape from the circulatory system...

(hemostasis).

In the inflammatory phase, bacteria and debris are phagocytosed and removed, and factors are released that cause the migration and division of cells involved in the proliferative phase.

The proliferative phase is characterized by angiogenesis

Angiogenesis

Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...

, collagen

Collagen

Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

deposition, granulation tissue

Granulation tissue

Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals...

formation, epithelialization, and wound contraction. In angiogenesis, new blood vessels are formed by vascular endothelial cells.
In fibroplasia and granulation tissue formation, fibroblast

Fibroblast

A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s grow and form a new, provisional extracellular matrix

Extracellular matrix

In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

(ECM) by excreting collagen and fibronectin. Concurrently, re-epithelialization of the epidermis occurs, in which epithelial cells proliferate and 'crawl' atop the wound bed, providing cover for the new tissue.

In contraction, the wound is made smaller by the action of myofibroblast

Myofibroblast

A Myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in differentiation.-Developmental origin:There are many possible ways of myofibroblast development:#Partial smooth muscle differentiation of a fibroblastic cell...

s, which establish a grip on the wound edges and contract themselves using a mechanism similar to that in smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.

In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

.

However, this process is not only complex but fragile, and susceptible to interruption or failure leading to the formation of non-healing chronic wound

Chronic wound

A chronic wound is a wound that does not heal in an orderly set of stages and in a predictable amount of time the way most wounds do; wounds that do not heal within three months are often considered chronic....

s. Factors which may contribute to this include diabetes, venous or arterial disease, old age, and infection.

Early vs cellular phase

As mentioned above, wound healing is classically divided into hemostasis, inflammation, proliferation, and remodeling. Although a useful construct, this model employs considerable overlapping among individual phases. Recently, a complementary model has been described, such that the many elements of wound healing are more-clearly delineated. The importance of this new model becomes more apparent through its utility in the fields of regenerative medicine

Regenerative medicine

Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore orestablish normal function". This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair...

and tissue engineering

Tissue engineering

Tissue engineering is the use of a combination of cells, engineering and materials methods, and suitable biochemical and physio-chemical factors to improve or replace biological functions...

(see Research and development section below). In this construct, the process of wound healing is divided into major two phases: early phase and cellular phase:

The early phase, which begins immediately following skin injury, involves cascading molecular and cellular events leading to hemostasis and formation of an early, makeshift extracellular matrix—providing structural support for cellular attachment and subsequent cellular proliferation.

The cellular phase follows the early phase, and involves several types of cells working together to mount an inflammatory response, synthesize granulation tissue, and restore the epithelial layer. Subdivisions of the cellular phase are: [1] Macrophage

Macrophage

Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and inflammatory components (within 1–2 days), [2] Epithelial-mesenchymal interaction: re-epithelialization (phenotype

Phenotype

A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...

change within hours, migration begins on day 1 or 2, [3] Fibroblasts and myofibroblasts: progressive alignment, collagen production, and matrix contraction (between day 4 day 14), [4] Endothelial cells and angiogenesis (begins on day 4), [5] Dermal matrix: elements of fabrication (begins on day 4, lasting 2 weeks) and alteration/remodeling (begins after week 2, lasting weeks to months—depending on wound size.).

Inflammatory phase

Just before the inflammatory phase is initiated, the clotting cascade takes place in order to obtain hemostasis

Hemostasis

, or stop blood loss by way of a fibrin clot. Thereafter, various soluble factors (including chemokines and cytokines) are released to attract cells

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

that phagocytise debris, bacteria, and damaged tissue, in addition to releasing signaling molecules that initiate the proliferative phase of wound healing.

Clotting cascade

When tissue

Tissue (biology)

Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

is first wounded, blood

Blood

Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....

comes in contact with collagen

Collagen

, triggering blood platelet

Platelet

Platelets, or thrombocytes , are small,irregularly shaped clear cell fragments , 2–3 µm in diameter, which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days...

s to begin secreting inflammatory factors. Platelets also express glycoprotein

Glycoprotein

Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...

s on their cell membrane

Cell membrane

The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

s that allow them to stick to one another and to aggregate, forming a mass.

Fibrin

Fibrin

Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

and fibronectin

Fibronectin

Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...

cross-link together and form a plug that traps protein

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s and particles and prevents further blood loss. This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited. Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors. The clot is eventually lysed and replaced with granulation tissue

Granulation tissue

and then later with collagen.

Platelets, the cells present in the highest numbers shortly after a wound occurs, release a number of things into the blood, including ECM proteins and cytokine

Cytokine

Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

s, including growth factor

Growth factor

A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....

s. Growth factors stimulate cells to speed their rate of division. Platelets also release other proinflammatory factors like serotonin

Serotonin

Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

, bradykinin

Bradykinin

Bradykinin is a peptide that causes blood vessels to dilate , and therefore causes blood pressure to lower. A class of drugs called ACE inhibitors, which are used to lower blood pressure, increase bradykinin further lowering blood pressure...

, prostaglandin

Prostaglandin

A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....

s, prostacyclin

Prostacyclin

Prostacyclin is a member of the family of lipid molecules known as eicosanoids.As a drug, it is also known as "epoprostenol". The terms are sometimes used interchangeably.-History:...

s, thromboxane

Thromboxane

Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring....

, and histamine

Histamine

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

, which serve a number of purposes, including to increase cell proliferation and migration to the area and to cause blood vessel

Blood vessel

The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s to become dilated and porous.

Vasoconstriction and vasodilation

Immediately after a blood vessel

Blood vessel

is breached, ruptured cell membrane

Cell membrane

s release inflammatory factors like thromboxane

Thromboxane

s and prostaglandin

Prostaglandin

s that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area. This vasoconstriction

Vasoconstriction

Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...

lasts five to ten minutes and is followed by vasodilation

Vasodilation

Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

, a widening of blood vessels, which peaks at about 20 minutes post-wounding. Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is histamine

Histamine

. Histamine also causes blood vessels to become porous, allowing the tissue to become edema

Edema

Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...

tous because proteins from the bloodstream leak into the extravascular space, which increases its osmolar load and draws water into the area. Increased porosity

Porosity

Porosity or void fraction is a measure of the void spaces in a material, and is a fraction of the volume of voids over the total volume, between 0–1, or as a percentage between 0–100%...

of blood vessels also facilitates the entry of inflammatory cells like leukocytes into the wound site from the bloodstream.

Polymorphonuclear neutrophils

Within an hour of wounding, polymorphonuclear neutrophil

Granulocyte

Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments...

s (PMNs) arrive at the wound site and become the predominant cells in the wound for the first two days after the injury occurs, with especially high numbers on the second day. They are attracted to the site by fibronectin, growth factors, and substances such as kinin

Kinin

A kinin is any of various structurally related polypeptides, such as bradykinin and kallikrein. They are members of the autacoid family.They act locally to induce vasodilation and contraction of smooth muscle.It is a component of the kinin-kallikrein system....

s. Neutrophils phagocytise debris and bacteria and also kill bacteria by releasing free radicals in what is called a 'respiratory burst

Respiratory burst

Respiratory burst is the rapid release of reactive oxygen species from different types of cells....

'. They also cleanse the wound by secreting protease

Protease

A protease is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein....

s that break down damaged tissue. Neutrophils usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by macrophage

Macrophage

s.

Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability. T cells also increase the activity of macrophages.

Macrophages

Macrophages are essential to wound healing. They replace PMNs as the predominant cells in the wound by two days after injury. Attracted to the wound site by growth factors released by platelets and other cells, monocyte

Monocyte

Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s from the bloodstream enter the area through blood vessel walls. Numbers of monocytes in the wound peak one to one and a half days after the injury occurs. Once they are in the wound site, monocytes mature into macrophages. The spleen

Spleen

The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

contains half the body's monocytes in reserve ready to be deployed to injured tissue.

The macrophage's main role is to phagocytize bacteria and damaged tissue, and they also debride damaged tissue by releasing proteases. Macrophages also secrete a number of factors such as growth factors and other cytokines, especially during the third and fourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to the area., although they may restrain the contraction phase. Macrophages are stimulated by the low oxygen

Oxygen

Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

content of their surroundings to produce factors that induce and speed angiogenesis

Angiogenesis

. and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellular matrix

Extracellular matrix

. By secreting these factors, macrophages contribute to pushing the wound healing process into the next phase.

Decline of inflammatory phase

As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site. These changes indicate that the inflammatory phase is ending and the proliferative phase is underway. In vitro evidence, obtained using the dermal equivalent

Dermal equivalent

The dermal equivalent is an in vitro model of the dermal layer of skin. It is constructed by seeding dermal fibroblasts into a collagen gel. This gel may then be allowed to contract as a model of wound contraction. This collagen gel contraction assay may be used to screen for treatments which...

model, suggests that the presence of macrophages actually delays wound contraction and thus the disappearance of macrophages from the wound may be essential for subsequent phases to occur.

Because inflammation plays roles in fighting infection, clearing debris and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to tissue

Tissue (biology)

damage if it lasts too long. Thus the reduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there is debris in the wound. Thus the presence of dirt or other objects can extend the inflammatory phase for too long, leading to a chronic wound

Chronic wound

Proliferative phase

About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase even before the inflammatory phase has ended. As in the other phases of wound healing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.

Angiogenesis

Also called neovascularization, the process of angiogenesis occurs concurrently with fibroblast proliferation when endothelial cells migrate to the area of the wound. Because the activity of fibroblasts and epithelial cells requires oxygen and nutrients, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythema

Erythema

Erythema is redness of the skin, caused by hyperemia of the capillaries in the lower layers of the skin. It occurs with any skin injury, infection, or inflammation...

tous) due to the presence of capillaries

Capillary

Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...

.

Stem cell

Stem cell

This article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...

s of endothelial cells, originating from parts of uninjured blood vessels, develop pseudopod

Pseudopod

Pseudopods or pseudopodia are temporary projections of eukaryotic cells. Cells that possess this faculty are generally referred to as amoeboids. Pseudopodia extend and contract by the reversible assembly of actin subunits into microfilaments...

ia and push through the ECM

Extracellular matrix

into the wound site to establish new blood vessels.

Endothelial cells are attracted to the wound area by fibronectin found on the fibrin scab and chemotactically

Chemotaxis

Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...

by angiogenic factors released by other cells, e.g. from macrophages and platelets when in a low-oxygen environment. Endothelial growth and proliferation is also directly stimulated by hypoxia

Hypoxia (medical)

Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...

, and presence of lactic acid

Lactic acid

Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...

in the wound.

To migrate, endothelial cells need collagenases and plasminogen activator

Plasminogen activator

A plasminogen activator is a serine protease which converts plasminogen to plasmin, thus promoting fibrinolysis.Types include:* Tissue plasminogen activator* Urokinase...

to degrade the clot and part of the ECM. Zinc

Zinc

Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...

-dependent metalloproteinase

Metalloproteinase

Metalloproteinases constitute a family of enzymes from the group of proteases, classified by the nature of the most prominent functional group in their active site. These are proteolytic enzymes whose catalytic mechanism involves a metal. Most metalloproteases are zinc-dependent, but some use...

s digest basement membrane

Basement membrane

The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...

and ECM to allow cell migration, proliferation and angiogenesis.

When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors. Thus, when tissue is adequately perfused

Perfusion

In physiology, perfusion is the process of nutritive delivery of arterial blood to a capillary bed in the biological tissue. The word is derived from the French verb "perfuser" meaning to "pour over or through."...

, migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by apoptosis

Apoptosis

Fibroplasia and granulation tissue formation

Simultaneously with angiogenesis, fibroblast

Fibroblast

A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...

s begin accumulating in the wound site. Fibroblasts begin entering the wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak at one to two weeks post-wounding. By the end of the first week, fibroblasts are the main cells in the wound Fibroplasia ends two to four weeks after wounding.

In the first two or three days after injury, fibroblasts mainly migrate and proliferate, while later, they are the main cells that lay down the collagen matrix in the wound site. Origins of these fibroblasts are thought to be from the adjacent uninjured cutaneous tissue (although new evidence suggests that some are derived from blood-borne, circulating adult stem cells/precursors). Initially fibroblasts utilize the fibrin cross-linking fibers (well-formed by the end of the inflammatory phase) to migrate across the wound, subsequently adhering to fibronectin. Fibroblasts then deposit ground substance

Ground substance

Ground substance is a term for the non-cellular components of extracellular matrix which contain the fibers.It is usually not visible on slides, because it is removed during the preparation process....

into the wound bed, and later collagen, which they can adhere to for migration.

Granulation tissue

Granulation tissue

functions as rudimentary tissue, and begins to appear in the wound already during the inflammatory phase, two to five days post wounding, and continues growing until the wound bed is covered. Granulation tissue consists of new blood vessels, fibroblasts, inflammatory cells, endothelial cells, myofibroblasts, and the components of a new, provisional extracellular matrix

Extracellular matrix

(ECM). The provisional ECM is different in composition from the ECM in normal tissue and its components originate from fibroblasts. Such components include fibronectin, collagen, glycosaminoglycan

Glycosaminoglycan

Glycosaminoglycans or mucopolysaccharides are long unbranched polysaccharides consisting of a repeating disaccharide unit. The repeating unit consists of a hexose or a hexuronic acid, linked to a hexosamine .-Production:Protein cores made in the rough endoplasmic reticulum are posttranslationally...

s, elastin

Elastin

Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...

, glycoprotein

Glycoprotein

s and proteoglycan

Proteoglycan

Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...

s. Its main components are fibronectin and hyaluronan

Hyaluronan

Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues...

, which create a very hydrated matrix and facilitate cell migration. Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue.

Growth factors (PDGF, TGF-β) and fibronectin encourage proliferation, migration to the wound bed, and production of ECM molecules by fibroblasts. Fibroblasts also secrete growth factors that attract epithelial cells to the wound site. Hypoxia also contributes to fibroblast proliferation and excretion of growth factors, though too little oxygen will inhibit their growth and deposition of ECM components, and can lead to excessive, fibrotic scarring.

Scar

Scars are areas of fibrous tissue that replace normal skin after injury. A scar results from the biological process of wound repair in the skin and other tissues of the body. Thus, scarring is a natural part of the healing process. With the exception of very minor lesions, every wound results in...

Collagen deposition

One of fibroblasts' most important duties is the production of collagen

Collagen

.

Collagen deposition is important because it increases the strength of the wound; before it is laid down, the only thing holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance to traumatic injury. Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.

Type III collagen and fibronectin

Fibronectin

are generally beginning to be produced in appreciable amounts at somewhere between approximately 10 hours and 3 days, depending mainly on wound size. Their deposition peaks at one to three weeks. They are the predominating tensile substances until the later phase of maturation, in which they are replaced by the stronger type I collagen.

Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly after wounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production and degradation become equal so there is no net collagen gain. This homeostasis signals the onset of the later maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done. At the end of the granulation phase, fibroblasts begin to commit apoptosis, converting granulation tissue from an environment rich in cells to one that consists mainly of collagen.

Epithelialization

The formation of granulation tissue in an open wound allows the reepithelialization phase to take place, as epithelial cells migrate across the new tissue to form a barrier between the wound and the environment. Basal keratinocyte

Keratinocyte

Keratinocytes are the predominant cell type in the epidermis, the outermost layer of the human skin, constituting 95% of the cells found there. Those keratinocytes found in the basal layer of the skin are sometimes referred to as "basal cells" or "basal keratinocytes"...

s from the wound edges and dermal appendages such as hair follicle

Hair follicle

A hair follicle is a skin organ that produces hair. Hair production occurs in phases, including a growth phase , and cessation phase , and a rest phase . Stem cells are principally responsible for the production of hair....

s, sweat glands and sebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing. They advance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in the middle.

Keratinocytes migrate without first proliferating. Migration can begin as early as a few hours after wounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must first be filled with granulation tissue. Thus the time of onset of migration is variable and may occur about one day after wounding. Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.

If the basement membrane is not breached, epithelial cells are replaced within three days by division and upward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin. However, if the basement membrane

Basement membrane

is ruined at the wound site, reepithelization must occur from the wound margins and from skin appendages such as hair follicles and sweat and oil glands that enter the dermis

Dermis

The dermis is a layer of skin between the epidermis and subcutaneous tissues, and is composed of two layers, the papillary and reticular dermis...

that are lined with viable keratinocytes. If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.

Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition

Contact inhibition

Contact inhibition is the natural process of arresting cell growth when two or more cells come into contact with each other. Oncologists use this property to distinguish between normal and cancerous cells....

and by chemicals such as nitric oxide

Nitric oxide

Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

. Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes, which normally anchor the cells by intermediate filaments in their cytoskeleton

Cytoskeleton

The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...

to other cells and to the ECM. Transmembrane receptor

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

protein

Protein

s called integrin

Integrin

Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....

s, which are made of glycoprotein

Glycoprotein

s and normally anchor the cell to the basement membrane by its cytoskeleton

Cytoskeleton

, are released from the cell's intermediate filaments and relocate to actin

Actin

Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...

filaments to serve as attachments to the ECM for pseudopod

Pseudopod

ia during migration. Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.

Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like lamellipodia

Pseudopod

and wide processes that look like ruffles. Actin

Actin

filaments and pseudopod

Pseudopod

ia form. During migration, integrin

Integrin

s on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along. The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and filopodia

Pseudopod

.

Epithelial cells climb over one another in order to migrate. This growing sheet of epithelial cells is often called the epithelial tongue. The first cells to attach to the basement membrane

Basement membrane

form the stratum basale. These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along as well. The more quickly this migration occurs, the less of a scar there will be.

Fibrin

Fibrin

Fibrin is a fibrous, non-globular protein involved in the clotting of blood. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot over a wound site....

, collagen, and fibronectin in the ECM may further signal cells to divide and migrate. Like fibroblasts, migrating keratinocytes use the fibronectin cross-linked with fibrin that was deposited in inflammation as an attachment site to crawl across.

As keratinocytes migrate, they move over granulation tissue but underneath the scab

Scab

Scab can refer to the following:* Scab, a hard coating on the skin formed during the wound healing reconstruction phase* Derogatory term for a strikebreaker, a person who works despite strike action or against the will of other employees...

(if one was formed), separating it from the underlying tissue. Epithelial cells have the ability to phagocytize debris such as dead tissue and bacterial matter that would otherwise obstruct their path. Because they must dissolve any scab that forms, keratinocyte migration is best enhanced by a moist environment, since a dry one leads to formation of a bigger, tougher scab. To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through. They secrete plasminogen activator

Plasminogen activator

A plasminogen activator is a serine protease which converts plasminogen to plasmin, thus promoting fibrinolysis.Types include:* Tissue plasminogen activator* Urokinase...

, which activates plasminogen, turning it into plasmin

Plasmin

Plasmin is an important enzyme present in blood that degrades many blood plasma proteins, most notably, fibrin clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein is encoded by the PLG gene.- Function :...

to dissolve the scab. Cells can only migrate over living tissue, so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolve damaged parts of the ECM in their way, particularly at the front of the migrating sheet. Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.

As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace them and to provide more cells for the advancing sheet. Proliferation behind migrating keratinocytes normally begins a few days after wounding and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues. Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.

Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytes themselves also produce and secrete factors, including growth factors and basement membrane proteins, which aid both in epithelialization and in other phases of healing. Growth factors are also important for the innate immune defense of skin wounds by stimulation of the production of antimicrobial peptides and neutrophil chemotactic cytokines in keratinocytes.

Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point contact inhibition

Contact inhibition

causes them to stop migrating. When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane. Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish desmosome

Desmosome

A desmosome , also known as macula adherens , is a cell structure specialized for cell-to-cell adhesion...

s and hemidesmosome

Hemidesmosome

Hemidesmosomes are very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. They are similar in form to desmosomes when visualized by electron microscopy. While desmosomes link two cells together, hemidesmosomes attach one cell to the...

s and become anchored once again to the basement membrane. Basal cells begin to divide and differentiate in the same manner as they do in normal skin to reestablish the strata found in reepithelialized skin.

Contraction

Contraction is a key phase of wound healing. If contraction continues for too long, it can lead to disfigurement and loss of function. Thus there is a great interest in understanding the biology of wound contraction, which can be modelled in vitro using the collagen gel contraction assay

Collagen gel contraction assay

The collagen gel contraction assay is a type of wound contraction. It is performed using the dermal equivalent model, which consists of dermal fibroblasts seeded into a collagen gel....

or the dermal equivalent

Dermal equivalent

model.

Contraction commences approximately a week after wounding, when fibroblasts have differentiated into myofibroblast

Myofibroblast

s In full thickness wounds, contraction peaks at 5 to 15 days post wounding. Contraction can last for several weeks and continues even after the wound is completely reepithelialized. A large wound can become 40 to 80% smaller after contraction. Wounds can contract at a speed of up to 0.75 mm per day, depending on how loose the tissue in the wounded area is. Contraction usually does not occur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization and alignment of cells with collagen.

At first, contraction occurs without myofibroblast involvement. Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction. Myofibroblasts contain the same kind of actin as that found in smooth muscle

Smooth muscle

Smooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...

cells.

Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrin in the provisional ECM in order to reach the wound edges. They form connections to the ECM at the wound edges, and they attach to each other and to the wound edges by desmosomes. Also, at an adhesion called the fibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrix like fibronectin and collagen. Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size. In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.

As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis. The breakdown of the provisional matrix leads to a decrease in hyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating and proliferating. These events signal the onset of the maturation stage of wound healing.

Maturation and remodeling

When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun. During maturation, type III collagen, which is prevalent during proliferation, is gradually degraded and the stronger type I collagen is laid down in its place. Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines. The onset of the maturation phase may vary extensively, depending on the size of the wound and whether it was initially closed or left open, ranging from approximately 3 days to 3 weeks The maturation phase can last for a year or longer, similarly depending on wound type.

As the phase progresses, the tensile strength

Tensile strength

Ultimate tensile strength , often shortened to tensile strength or ultimate strength, is the maximum stress that a material can withstand while being stretched or pulled before necking, which is when the specimen's cross-section starts to significantly contract...

of the wound increases, with the strength approaching 50% that of normal tissue

Tissue (biology)

by three months after injury and ultimately becoming as much as 80% as strong as normal tissue. Since activity at the wound site is reduced, the scar loses its red appearance as blood vessel

Blood vessel

s that are no longer needed are removed by apoptosis

Apoptosis

.

The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing may progress inappropriately to either a chronic wound

Chronic wound

such as a venous ulcer

Venous ulcer

Venous ulcers are wounds that are thought to occur due to improper functioning of venous valves, usually of the legs. They are the major cause of chronic wounds, occurring in 70% to 90% of chronic wound cases...

or pathological scarring such as a keloid scar.

Research and development

Up until a decade ago, the classic paradigm of wound healing, involving stem cells restricted to organ-specific lineages, had never been seriously challenged. Since then, the notion of adult stem cells having cellular plasticity or the ability to differentiate into non-lineage cells has emerged as an alternative explanation. To be more specific, hematopoietic progenitor cells (that give rise to mature cells in the blood) may have the ability de-differentiate back into hematopoietic stem cells and/or transdifferentiate into non-lineage cells, such as fibroblasts.

Stem cells and cellular plasticity

Multipotent adult stem cells have the capacity to be self-renewing and give rise to different cell types. Stem cells give rise to progenitor cells, which are cells that are not self-renewing, but can generate several types of cells. The extent of stem cell involvement in cutaneous (skin) wound healing is complex and not fully understood.

It is thought that the epidermis and dermis are reconstituted by mitotically active stem cells that reside at the apex of rete ridges (basal stem cells or BSC), the bulge of hair follicle

Hair follicle

s (hair follicular stem cell or HFSC), and the papillary dermis (dermal stem cells). Moreover, bone marrow may also contain stem cells that play a major role in cutaneous wound healing.

In rare circumstances, such as extensive cutaneous injury, self-renewal subpopulations in the bone marrow are induced to participate in the healing process, whereby they give rise to collagen-secreting cells that seem to play a role during wound repair. These two self-renewal subpopulations are (1) bone marrow-derived mesenchymal stem cells (MSC) and (2) hematopoietic stem cells (HSC). Bone marrow also harbors a progenitor subpopulation (endothelial progenitor cells or EPC) that, in the same type of setting, are mobilized to aid in the reconstruction of blood vessels. Moreover, it thought that, extensive injury to skin also promotes the early trafficking of a unique subclass of leukocytes (circulating fibrocyte

Fibrocyte

A fibrocyte is an inactive mesenchymal cell, that is, a cell showing minimal cytoplasm, limited amounts of rough endoplasmic reticulum and lacks biochemical evidence of protein synthesis.The term fibrocyte contrasts with the term fibroblast...

s) to the injured region, where they perform various functions related to wound healing.

Wound repair versus regeneration

There is a subtle distinction between ‘repair’ and ‘regeneration'. An injury is an interruption of morphology and/or functionality of a given tissue. Repair refers to the physiologic adaptation of an organ after injury in an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue. True tissue regeneration

Regeneration (biology)

In biology, regeneration is the process of renewal, restoration, and growth that makes genomes, cells, organs, organisms, and ecosystems resilient to natural fluctuations or events that cause disturbance or damage. Every species is capable of regeneration, from bacteria to humans. At its most...

refers to the replacement of lost/damaged tissue with an ‘exact’ copy, such that both morphology and functionality are completely restored. Mammals do not regenerate spontaneously. In some instances, such as skin, ‘partial regeneration’ may be induced by the use of biodegradable (collagen

Collagen

-glycoaminoglycan) scaffolds. These scaffolds are structurally analogous to extracellular matrix

Extracellular matrix

(ECM) found in normal/un-injured dermis. Interestingly, fundamental conditions required for tissue regeneration often oppose conditions that favor efficient wound repair, including inhibition of (1) platelet activation, (2) inflammatory response, and (3) wound contraction. In addition to providing support for fibroblast and endothelial cell attachment, biodegradable scaffolds inhibit wound contraction, thereby allowing the healing process to proceed towards a more-regenerative/less-scarring pathway. Pharmaceutical agents have been investigated which may be able to turn off myofibroblast

Myofibroblast

differentiation

A new way of thinking derived from the notion that heparan sulfate

Heparan sulfate

Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...

s are key player in tissue homeostasis: the process that makes the tissue replace dead cells by identical cells. In wound areas, tissue homeostasis is lost as the heparan sulfates are degraded preventing the replacement of dead cells by identical cells. Heparan sulfate analogue

Heparan sulfate analogue

Heparan sulfate analogues are polymers engineered to mimic several properties of heparan sulfates. They can be constituted with a backbone of polysaccharides, such as poly glucose or glucuronates or a polyester such as co polymers of lactic or malic acid to which sulfates, sulfonate or...

s cannot be degraded by all know heparanases and glycanases and bind to the free heparin sulfate binding spots on the ECM, therefore preserving the normal tissue homeostasis and preventing scarring.

Primary intention

involves epidermis and dermis without total penetration of dermis
healing by process of epithelialization

When wound edges are brought together so that they are adjacent to each other (re-approximated)
Minimizes scarring
Most surgical wounds heal by primary intention healing
Wound closure is performed with sutures (stitches), staples, or adhesive tape
Examples: well-repaired lacerations, well reduced bone fracture
Bone fracture
A bone fracture is a medical condition in which there is a break in the continuity of the bone...

s, healing after flap surgery

Secondary intention

The wound is allowed to granulate
Surgeon may pack the wound with a gauze or use a drainage system
Granulation results in a broader scar
Healing process can be slow due to presence of drainage from infection
Wound care must be performed daily to encourage wound debris removal to allow for granulation tissue formation
Examples: gingivectomy
Gingivectomy
A gingivectomy is a periodontal surgical procedure which includes the removal of gingival tissue in order to achieve a more aesthetic appearance and/or functional contour. The procedure is particularly useful if the gingival tissues have become enlarged, e.g. due to certain medications...

, gingivoplasty
Gingivoplasty
Gingivoplasty is the process by which the gingiva are reshaped to correct deformities....

, tooth extraction sockets, poorly reduced fractures.

Tertiary intention

(Delayed primary closure or secondary suture):

The wound is initially cleaned, debrided and observed, typically 4 or 5 days before closure.
The wound is purposely left open
Examples: healing of wounds by use of tissue grafts.

If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This type of healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminated tissues is well underway, and the processes of epithelization, collagen deposition, and maturation are occurring. Foreign materials are walled off by macrophages that may metamorphose into epithelioid cells, which are encircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at this juncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting in prominent scarring.

Overview of involved growth factors

Following are the main growth factors involved in wound healing:

Growth factor	Abbreviation	Main origins	Effects
Epidermal growth factor Epidermal growth factor Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...	EGF	Activated macrophages Salivary glands Keratinocytes	Keratinocyte and fibroblast mitogen Mitogen A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen.... Keratinocyte migration Granulation tissue Granulation tissue Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size it heals... formation
Transforming growth factor-α	TGF-α	Activated macrophages T-lymphocytes Keratinocytes	Hepatocyte Hepatocyte A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates... and epithelial cell proliferation Expression of antimicrobial peptides Expression of chemotactic cytokines
Hepatocyte growth factor Hepatocyte growth factor Hepatocyte growth factor/scatter factor is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells...	HGF	Mesenchymal cells	Epithelial and endothelial cell proliferation Hepatocyte motility
Vascular endothelial growth factor Vascular endothelial growth factor Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....	VEGF	Mesenchymal cells	Vascular permeability Endothelial cell proliferation
Platelet derived growth factor	PDGF	Platelets Macrophages Endothelial cells Smooth muscle cells Keratinocytes	Granulocyte Granulocyte Granulocytes are a category of white blood cells characterized by the presence of granules in their cytoplasm. They are also called polymorphonuclear leukocytes because of the varying shapes of the nucleus, which is usually lobed into three segments... , macrophage, fibroblast and smooth muscle cell chemotaxis Chemotaxis Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,... Granulocyte, macrophage and fibroblast activation Fibroblast, endothelial cell and smooth muscle cell proliferation Matrix metalloproteinase Matrix metalloproteinase Matrix metalloproteinases are zinc-dependent endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.... , fibronectin Fibronectin Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans... and hyaluronan Hyaluronan Hyaluronan is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues... production Angiogenesis Wound remodeling Integrin expression regulation
Fibroblast growth factor Fibroblast growth factor Fibroblast growth factors, or FGFs, are a family of growth factors involved in angiogenesis, wound healing, and embryonic development. The FGFs are heparin-binding proteins and interactions with cell-surface associated heparan sulfate proteoglycans have been shown to be essential for FGF signal... 1 and 2	FGF-1, -2	Macrophages Mast cell Mast cell A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin... s T-lymphocytes Endothelial cells Fibroblasts	Fibroblast chemotaxis Fibroblast and keratinocyte proliferation Keratinocyte migration Angiogenesis Wound contraction matrix deposition
Transforming growth factor-β	TGF-β	Platelets T-lymphocytes Macrophages Endothelial cells Keratinocytes Smooth muscle cells Fibroblasts	Granulocyte, macrophage, lymphocyte, fibroblast and smooth muscle cell chemotaxis TIMP Tissue inhibitor of metalloproteinases The matrix metalloproteinases are inhibited by specific endogenous tissue inhibitors of metalloproteinases , which comprise a family of four protease inhibitors: TIMP1, TIMP2, TIMP3 and TIMP4.... synthesis Angiogenesis Fibroplasia Matrix metalloproteinase production inhibition Keratinocyte proliferation
Keratinocyte growth factor Keratinocyte Growth Factor The Keratinocyte Growth Factor , also known as FGF7, is a growth factor present in the epithelialization-phase of wound healing. In this phase, keratinocytes are covering the wound, forming the epithelium....	KGF	Keratinocytes	Keratinocyte migration, proliferation and differentiation
Unless else specified in boxes, then reference is:

External links

Orgill D.P. Wound Healing and Tissue Engineering Laboratory Harvard Medical School, Brigham & Women's Hospital.
Ingber D. How wounds heal and tumors form Children's Hospital Boston research department.
Mustoe T. 2005. Dermal ulcer healing: Advances in understanding. Presented at meeting: Tissue repair and ulcer/wound healing: molecular mechanisms,therapeutic targets and future directions. Paris, France, March 17–18, 2005. Accessed December 31, 2006.
Revis D.R. and Seagel M.B. 2006. Skin, Grafts. Emedicine.com. Accessed December 31, 2006.
Stillman R.M. 2006. Wound Care. Emedicine.com. Accessed December 31, 2006.
Wilhelmi B.J. 2006. Wound Healing, widened and hypertrophic scars. Emedicine.com. Accessed December 31, 2006.
Journal of Burns and Wounds http://www.journalofburnsandwounds.com
Fibrogenesis & Tissue Repair, an online open access journal about chronic wound healing and fibrogenesis.
Phases of Wound Healing video from the American Medical Videos Journal
EWMA Journal, Journal of the European Wound Management Association

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