Hand abrasion

Approximate days since injury0 3 17 30

Wound healingFrom Wikipedia, the free encyclopedia

Wound healing is an intricate processwhere the skin (or another organ-tissue)repairs itself after injury.[1] In normal skin,the epidermis (outermost layer) and dermis(inner or deeper layer) exist in a steady-state equilibrium, forming a protectivebarrier against the external environment.Once the protective barrier is broken, thenormal (physiologic) process of woundhealing is immediately set in motion. Theclassic model of wound healing is divided into three or four sequential, yet overlapping,[2] phases: (1)hemostasis (not considered a phase by some authors), (2) inflammation, (3) proliferation and (4) remodeling.[3]Upon injury to the skin, a set of complex biochemical events takes place in a closely orchestrated cascade torepair the damage.[2]

Within the first few minutes after the injury, platelets adhere to the site of injury, become activated, andaggregate (join together); followed by activation of the coagulation cascade which forms a clot of aggregatedplatelets in a mesh of cross-linked fibrin protein. This clot stops active bleeding (hemostasis).[4][5]

During the inflammation phase, bacteria and cell debris are phagocytosed and removed from the wound bywhite blood cells. Platelet-derived growth factors (stored in the alpha granules of the platelets) are released intothe wound that cause the migration and division of cells during the proliferative phase.

The proliferation phase is characterized by angiogenesis, collagen deposition, granulation tissue formation,epithelialization, and wound contraction.[6] In angiogenesis, vascular endothelial cells form new bloodvessels.[7] In fibroplasia and granulation tissue formation, fibroblasts grow and form a new, provisionalextracellular matrix (ECM) by excreting collagen and fibronectin.[6] Concurrently, re-epithelialization of theepidermis occurs, in which epithelial cells proliferate and 'crawl' atop the wound bed, providing cover for thenew tissue.[8]

During wound contraction, myofibroblasts decrease the size of the wound by gripping the wound edges andcontracting using a mechanism that resembles that in smooth muscle cells. When the cells' roles are close tocomplete, unneeded cells undergo apoptosis.[6]

During maturation and remodeling, collagen is remodeled and realigned along tension lines, and cells that areno longer needed are removed by apoptosis.

However, this process is not only complex but fragile, and is susceptible to interruption or failure leading to theformation of non-healing chronic wounds. Factors that contribute to non-healing chronic wounds are diabetes,venous or arterial disease, infection, and metabolic deficiencies of old age.[9]

Approximate times of the different phases of wound healing,[10] with faded intervals marking substantial variation,depending mainly on wound size and healing conditions, but image does not include major impairments that cause chronicwounds.

Contents1 Early vs cellular phase2 Timing and reepithelialization3 Inflammatory phase

3.1 Clotting cascade3.2 Vasoconstriction and vasodilation3.3 Polymorphonuclear neutrophils3.4 Macrophages3.5 Decline of inflammatory phase

4 Proliferative phase4.1 Angiogenesis4.2 Fibroplasia and granulation tissue formation

4.2.1 Collagen deposition4.3 Epithelialization4.4 Contraction

5 Maturation and remodeling6 Factors affecting wound healing

6.1 Local factors6.2 Systemic factors

7 Research and development7.1 Stem cells and cellular plasticity7.2 Wound repair versus regeneration7.3 Scarless wound healing

8 Simulating wound healing from a growth perspective9 Wound closure intentions

A fluorescence micrograph of cells inDrosophila larvae healing after a puncturewound. The arrow points to cells that havefused to form syncytia, and the arrowheadspoint to cells that are oriented to face thewound.[11]

9.1 Primary intention9.2 Secondary intention9.3 Tertiary intention

10 Overview of involved growth factors10.1 Complications of Wound Healing

11 See also12 Notes and references13 External links

Early vs cellular phaseWound healing is classically divided into hemostasis, inflammation,proliferation, and remodeling. Although a useful construct, thismodel employs considerable overlapping among individual phases.A complementary model has recently been described[1] where themany elements of wound healing are more clearly delineated. Theimportance of this new model becomes more apparent through itsutility in the fields of regenerative medicine and tissue engineering(see Research and development section below). In this construct,the process of wound healing is divided into two major phases: theearly phase and the cellular phase:[1]

The early phase, which begins immediately following skin injury,involves cascading molecular and cellular events leading tohemostasis and formation of an early, makeshift extracellular matrixthat provides structural staging for cellular attachment andsubsequent cellular proliferation.

The cellular phase involves several types of cells working together to mount an inflammatory response,synthesize granulation tissue, and restore the epithelial layer.[1] Subdivisions of the cellular phase are: [1]Macrophages and inflammatory components (within 12 days), [2] Epithelial-mesenchymal interaction: re-epithelialization (phenotype change within hours, migration begins on day 1 or 2), [3] Fibroblasts andmyofibroblasts: 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 day4, lasting 2 weeks) and alteration/remodeling (begins after week 2, lasting weeks to monthsdepending onwound size).[1]

Timing and reepithelialization

Timing is important to wound healing. Critically, the timing of wound reepithelialization can decide theoutcome of the healing.[12] If the epithelization of tissue over a denuded area is slow, a scar will form overmany weeks, or months;[13][14] If the epithelization of a wounded area is fast, the healing will result inregeneration.[14]

Inflammatory phaseJust before the inflammatory phase is initiated, the clotting cascade occurs in order to achieve hemostasis, orstop blood loss by way of a fibrin clot. Thereafter, various soluble factors (including chemokines and cytokines)are released to attract cells that phagocytise debris, bacteria, and damaged tissue, in addition to releasingsignaling molecules that initiate the proliferative phase of wound healing.

Clotting cascadeWhen tissue is first wounded, blood comes in contact with collagen, triggering blood platelets to begin secretinginflammatory factors.[15] Platelets also express sticky glycoproteins on their cell membranes that allow them toaggregate, forming a mass.[6]

Fibrin and fibronectin cross-link together and form a plug that traps proteins and particles and prevents furtherblood loss.[16] This fibrin-fibronectin plug is also the main structural support for the wound until collagen isdeposited.[6] Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secretefactors.[6] The clot is eventually lysed and replaced with 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 intothe blood, including cytokines and growth factors.[15] Growth factors stimulate cells to speed their rate ofdivision. Platelets also release other proinflammatory factors like serotonin, bradykinin, prostaglandins,prostacyclins, thromboxane, and histamine,[2] which serve a number of purposes, including to increase cellproliferation and migration to the area and to cause blood vessels to become dilated and porous. In many ways,extravasated platelets in trauma perform a similar function to tissue macrophages and mast cells exposed tomicrobial molecular signatures in infection - they become activated, and secrete molecular mediators thatinitiate the inflammatory process. Vasoactive amines, eicosanoids, cytokines.

Vasoconstriction and vasodilationImmediately after a blood vessel is breached, ruptured cell membranes release inflammatory factors likethromboxanes and prostaglandins that cause the vessel to spasm to prevent blood loss and to collectinflammatory cells and factors in the area.[2] This vasoconstriction lasts five to ten minutes and is followed byvasodilation, a widening of blood vessels, which peaks at about 20 minutes post-wounding.[2] Vasodilation isthe end result of factors released by platelets and other cells. The main factor involved in causing vasodilation ishistamine.[2][15] Histamine also causes blood vessels to become porous, allowing the tissue to becomeedematous because proteins from the bloodstream leak into the extravascular space, which increases its osmolarload and draws water into the area.[2] Increased porosity of blood vessels also facilitates the entry ofinflammatory cells like leukocytes into the wound site from the bloodstream.[17][18]

Polymorphonuclear neutrophilsWithin an hour of wounding, polymorphonuclear neutrophils (PMNs) arrive at the wound site and become thepredominant cells in the wound for the first two days after the injury occurs, with especially high numbers onthe second day.[19] They are attracted to the site by fibronectin, growth factors, and substances such as kinins.Neutrophils phagocytise debris and kill bacteria by releasing free radicals in what is called a 'respiratoryburst.[20][21] They also cleanse the wound by secreting proteases that break down damaged tissue. Functionalneutrophils at the wound site only have life-spans of around 2 days, so they usually undergo apoptosis once theyhave completed their tasks and are engulfed and degraded by macrophages.[22]

Other leukocytes to enter the area include helper T cells, which secrete cytokines to cause more T cells to divideand to increase inflammation and enhance vasodilation and vessel permeability.[17][23] T cells also increase theactivity of macrophages.[17]

Macrophages

One of the macrophage's roles is to phagocytize other expended phagocytes,[24] bacteria and damaged tissue,[19]and they also debride damaged tissue by releasing proteases.[25]

Macrophages function in regeneration[26][27] and are essential for wound healing.[19] They are stimulated by thelow oxygen content of their surroundings to produce factors that induce and speed angiogenesis[20] and theyalso stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new extracellularmatrix.[28][29] By secreting these factors, macrophages contribute to pushing the wound healing process into thenext phase. They replace PMNs as the predominant cells in the wound by two days after injury.[24]

The spleen contains half the body's monocytes in reserve ready to be deployed to injured tissue.[30][31] Attractedto the wound site by growth factors released by platelets and other cells, monocytes from the bloodstream enterthe area through blood vessel walls.[32] Numbers of monocytes in the wound peak one to one and a half daysafter the injury occurs.[23] Once they are in the wound site, monocytes mature into macrophages. Macrophagesalso secrete a number of factors such as growth factors and other cytokines, especially during the third andfourth post-wounding days. These factors attract cells involved in the proliferation stage of healing to thearea.[15]

In wound healing that result in incomplete repair, scar contraction occurs, bringing varying gradations ofstructural imperfections, deformities and problems with flexibility.[33] Macrophages may restrain thecontraction phase.[27] Scientists have reported that removing the macrophages from a salamander resulted infailure of a typical regeneration response (limb regeneration), instead bringing on a repair (scarring)response.[34][35]

Decline of inflammatory phase

As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, andnumbers of neutrophils and macrophages are reduced at the wound site.[19] These changes indicate that theinflammatory phase is ending and the proliferative phase is underway.[19] In vitro evidence, obtained using thedermal equivalent model, suggests that the presence of macrophages actually delays wound contraction and thusthe disappearance of macrophages from the wound may be essential for subsequent phases to occur.[27]

Because inflammation plays roles in fighting infection, clearing debris and inducing the proliferation phase, it isa necessary part of healing. However, inflammation can lead to tissue damage if it lasts too long.[6] Thus thereduction of inflammation is frequently a goal in therapeutic settings. Inflammation lasts as long as there isdebris in the wound. Thus, if the individual's immune system is compromised and is unable to clear the debrisfrom the wound and/or if excessive detritus, devitalized tissue, or microbial biofilm is present in the wound,these factors may cause a prolonged inflammatory phase and prevent the wound from properly commencing theproliferation phase of healing. This can lead to a chronic wound.

Proliferative phaseAbout two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset ofthe proliferative phase even before the inflammatory phase has ended.[36] As in the other phases of woundhealing, steps in the proliferative phase do not occur in a series but rather partially overlap in time.

Angiogenesis

Also called neovascularization,[37] the process of angiogenesis occurs concurrently with fibroblast proliferationwhen endothelial cells migrate to the area of the wound.[38] Because the activity of fibroblasts and epithelialcells requires oxygen and nutrients, angiogenesis is imperative for other stages in wound healing, like epidermaland fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is erythematous)due to the presence of capillaries.[38]

Angiogenesis occurs in overlapping phases in response to inflammation:

1. Latent period: During the haemostatic and inflammatory phase of the wound healing process, vasodilationand permeabilisation allow leukocyte extravasation and phagocytic debridement and decontamination of thewound area. Tissue swelling aids later angiogenesis by expanding and loosening the existing collagenousextracellular matrix.

2. Endothelial activation: As the wound macrophages switches from inflammatory to healing mode, it beginsto secrete endothelial chemotactic and growth factors to attract adjacent endothelial cells. Activated endothelialcells respond by retracting and reducing cell junctions, loosening themselves from their embedded endothelium.Characteristically the activated endothelial cells show enlarged nucleoli.

3. Degradation of endothelial basement membrane: The wound macrophages, mast cells and the endothelialcells themselves secrete proteases to break down existing vascular basal lamina.

4. Vascular sprouting: With the breakdown of endothelial basement membrane, detached endothelial cellsfrom pre-existing capillaries and post-capillary venues can divide and migrate chemotactically towards thewound, laying down new vessels in the process. Vascular sprouting can be aided by ambient hypoxia andacidosis in the wound environment, as hypoxia stimulates the endothelial transcription factor, hypoxia induciblefactor (HIF) to transactivate angiogenic genes such as VEGF and GLUT1. Sprouted vessels can self-organiseinto luminal morphologies, and fusion of blind channels give rise to new capillary networks.

5. Vascular maturation: the endothelium of vessels mature by laying down new endothelial extracellularmatrix, followed by basal lamina formation. Lastly the vessel establishes a pericyte layer.

Stem cells of endothelial cells, originating from parts of uninjured blood vessels, develop pseudopodia and pushthrough the ECM into the wound site to establish new blood vessels.[20]

Endothelial cells are attracted to the wound area by fibronectin found on the fibrin scab and chemotactically byangiogenic factors released by other cells,[39] e.g. from macrophages and platelets when in a low-oxygenenvironment. Endothelial growth and proliferation is also directly stimulated by hypoxia, and presence of lacticacid in the wound.[36] For example, hypoxia stimulates the endothelial transcription factor, hypoxia-induciblefactor (HIF) to transactivate a set of proliferative genes including vascular endothelial growth factor (VEGF)and glucose transporter 1 (GLUT1).

To migrate, endothelial cells need collagenases and plasminogen activator to degrade the clot and part of theECM.[2][19] Zinc-dependent metalloproteinases digest basement membrane and ECM to allow cell migration,proliferation and angiogenesis.[40]

When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filledenvironment, they stop producing angiogenic factors.[20] Thus, when tissue is adequately perfused, migrationand proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die byapoptosis.[39]

Fibroplasia and granulation tissue formationSimultaneously with angiogenesis, fibroblasts begin accumulating in the wound site. Fibroblasts begin enteringthe wound site two to five days after wounding as the inflammatory phase is ending, and their numbers peak atone to two weeks post-wounding.[19] By the end of the first week, fibroblasts are the main cells in the wound.[2]Fibroplasia ends two to four weeks after wounding.

As a model the mechanism of fibroplasia may be conceptualised as an analogous process to angiogenesis (seeabove) - only the cell type involved is fibroblasts rather than endothelial cells. Initially there is a latent phasewhere the wound undergoes plasma exudation, inflammatory decontamination and debridement. Oedemaincreases the wound histologic accessibility for later fibroplastic migration. Second, as inflammation nearscompletion, macrophage and mast cells release fibroblast growth and chemotactic factors to activate fibroblastsfrom adjacent tissue. Fibroblasts at this stage loosen themselves from surrounding cells and ECM. Phagocytesfurther release proteases that break down the ECM of neighbouring tissue, freeing the activated fibroblasts toproliferate and migrate towards the wound. The difference between vascular sprouting and fibroblast

proliferation is that the former is enhanced by hypoxia, whilst the latter is inhibited by hypoxia. The depositedfibroblastic connective tissue matures by secreting ECM into the extracellular space, forming granulation tissue(see below). Lastly collagen is deposited into the ECM.

In the first two or three days after injury, fibroblasts mainly migrate and proliferate, while later, they are themain cells that lay down the collagen matrix in the wound site.[2] Origins of these fibroblasts are thought to befrom the adjacent uninjured cutaneous tissue (although new evidence suggests that some are derived fromblood-borne, circulating adult stem cells/precursors).[41] Initially fibroblasts utilize the fibrin cross-linking fibers(well-formed by the end of the inflammatory phase) to migrate across the wound, subsequently adhering tofibronectin.[39] Fibroblasts then deposit ground substance into the wound bed, and later collagen, which theycan adhere to for migration.[15]

Granulation tissue functions as rudimentary tissue, and begins to appear in the wound already during theinflammatory 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 (ECM). The provisional ECM isdifferent in composition from the ECM in normal tissue and its components originate from fibroblasts.[28] Suchcomponents include fibronectin, collagen, glycosaminoglycans, elastin, glycoproteins and proteoglycans.[39] Itsmain components are fibronectin and hyaluronan, which create a very hydrated matrix and facilitate cellmigration.[32] Later this provisional matrix is replaced with an ECM that more closely resembles that found innon-injured tissue.

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

Collagen deposition

One of fibroblasts' most important duties is the production of collagen.[38]

Collagen deposition is important because it increases the strength of the wound; before it is laid down, the onlything holding the wound closed is the fibrin-fibronectin clot, which does not provide much resistance totraumatic injury.[20] Also, cells involved in inflammation, angiogenesis, and connective tissue constructionattach to, grow and differentiate on the collagen matrix laid down by fibroblasts.[42]

Type III collagen and fibronectin are generally beginning to be produced in appreciable amounts at somewherebetween approximately 10 hours[43] and 3 days,[39] depending mainly on wound size. Their deposition peaks atone to three weeks.[28] They are the predominating tensile substances until the later phase of maturation, inwhich they are replaced by the stronger type I collagen.

Even as fibroblasts are producing new collagen, collagenases and other factors degrade it. Shortly afterwounding, synthesis exceeds degradation so collagen levels in the wound rise, but later production anddegradation become equal so there is no net collagen gain.[20] This homeostasis signals the onset of the latermaturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once theirwork is done.[44] At the end of the granulation phase, fibroblasts begin to commit apoptosis, convertinggranulation tissue from an environment rich in cells to one that consists mainly of collagen.[2]

EpithelializationThe formation of granulation tissue into an open wound allows the reepithelialization phase to take place, asepithelial cells migrate across the new tissue to form a barrier between the wound and the environment.[39]Basal keratinocytes from the wound edges and dermal appendages such as hair follicles, sweat glands andsebacious (oil) glands are the main cells responsible for the epithelialization phase of wound healing.[44] Theyadvance in a sheet across the wound site and proliferate at its edges, ceasing movement when they meet in themiddle. In healing that results in a scar, sweat glands, hair follicles[45][46] and nerves do not form. With the lackof hair follicles, nerves and sweat glands, the wound, and the resulting healing scar, provide a challenge to thebody with regards to temperature control.[46]

Keratinocytes migrate without first proliferating.[47] Migration can begin as early as a few hours afterwounding. However, epithelial cells require viable tissue to migrate across, so if the wound is deep it must firstbe filled with granulation tissue.[48] Thus the time of onset of migration is variable and may occur about oneday after wounding.[49] Cells on the wound margins proliferate on the second and third day post-wounding inorder to provide more cells for migration.[28]

If the basement membrane is not breached, epithelial cells are replaced within three days by division andupward migration of cells in the stratum basale in the same fashion that occurs in uninjured skin.[39] However,if the basement membrane is ruined at the wound site, reepithelization must occur from the wound margins andfrom skin appendages such as hair follicles and sweat and oil glands that enter the dermis that are lined withviable keratinocytes.[28] If the wound is very deep, skin appendages may also be ruined and migration can onlyoccur from wound edges.[48]

Migration of keratinocytes over the wound site is stimulated by lack of contact inhibition and by chemicals suchas nitric oxide.[50] Before they begin to migrate, cells must dissolve their desmosomes and hemidesmosomes,which normally anchor the cells by intermediate filaments in their cytoskeleton to other cells and to theECM.[23] Transmembrane receptor proteins called integrins, which are made of glycoproteins and normallyanchor the cell to the basement membrane by its cytoskeleton, are released from the cell's intermediate filamentsand relocate to actin filaments to serve as attachments to the ECM for pseudopodia during migration.[23] Thuskeratinocytes detach from the basement membrane and are able to enter the wound bed.[36]

Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellularprocesses like lamellipodia and wide processes that look like ruffles.[32] Actin filaments and pseudopodiaform.[36] During migration, integrins on the pseudopod attach to the ECM, and the actin filaments in the

A scab covering a healing wound

projection pull the cell along.[23] The interaction with molecules in the ECM through integrins further promotesthe formation of actin filaments, lamellipodia, and filopodia.[23]

Epithelial cells climb over one another in order to migrate.[44] This growing sheet of epithelial cells is oftencalled the epithelial tongue.[47] The first cells to attach to the basement membrane form the stratum basale.These basal cells continue to migrate across the wound bed, and epithelial cells above them slide along aswell.[47] The more quickly this migration occurs, the less of a scar there will be.[51]

Fibrin, 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 anattachment site to crawl across.[25][32][44]

As keratinocytes migrate, they move over granulation tissue butunderneath the scab (if one was formed), separating it from theunderlying tissue.[44][49] Epithelial cells have the ability to phagocytizedebris such as dead tissue and bacterial matter that would otherwiseobstruct their path. Because they must dissolve any scab that forms,keratinocyte migration is best enhanced by a moist environment, since adry one leads to formation of a bigger, tougher scab.[25][39][44][52] Tomake their way along the tissue, keratinocytes must dissolve the clot,debris, and parts of the ECM in order to get through.[49][53] They secreteplasminogen activator, which activates plasminogen, turning it intoplasmin to dissolve the scab. Cells can only migrate over livingtissue,[44] so they must excrete collagenases and proteases like matrix metalloproteinases (MMPs) to dissolvedamaged parts of the ECM in their way, particularly at the front of the migrating sheet.[49] Keratinocytes alsodissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.[23]

As keratinocytes continue migrating, new epithelial cells must be formed at the wound edges to replace themand to provide more cells for the advancing sheet.[25] Proliferation behind migrating keratinocytes normallybegins a few days after wounding[48] and occurs at a rate that is 17 times higher in this stage of epithelializationthan in normal tissues.[25] Until the entire wound area is resurfaced, the only epithelial cells to proliferate are atthe wound edges.[47]

Growth factors, stimulated by integrins and MMPs, cause cells to proliferate at the wound edges. Keratinocytesthemselves also produce and secrete factors, including growth factors and basement membrane proteins, whichaid both in epithelialization and in other phases of healing.[54] Growth factors are also important for the innateimmune defense of skin wounds by stimulation of the production of antimicrobial peptides and neutrophilchemotactic cytokines in keratinocytes.

Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at whichpoint contact inhibition causes them to stop migrating.[32] When they have finished migrating, the keratinocytessecrete the proteins that form the new basement membrane.[32] Cells reverse the morphological changes they

underwent in order to begin migrating; they reestablish desmosomes and hemidesmosomes and becomeanchored once again to the basement membrane.[23] Basal cells begin to divide and differentiate in the samemanner as they do in normal skin to reestablish the strata found in reepithelialized skin.[32]

ContractionContraction is a key phase of wound healing with repair. If contraction continues for too long, it can lead todisfigurement and loss of function.[33] Thus there is a great interest in understanding the biology of woundcontraction, which can be modelled in vitro using the collagen gel contraction assay or the dermal equivalentmodel.[27][55]

Contraction commences approximately a week after wounding, when fibroblasts have differentiated intomyofibroblasts [56] In full thickness wounds, contraction peaks at 5 to 15 days post wounding.[39] Contractioncan last for several weeks[48] and continues even after the wound is completely reepithelialized.[2] A largewound can become 40 to 80% smaller after contraction.[32][44] Wounds can contract at a speed of up to0.75 mm per day, depending on how loose the tissue in the wounded area is.[39] Contraction usually does notoccur symmetrically; rather most wounds have an 'axis of contraction' which allows for greater organization andalignment of cells with collagen.[56]

At first, contraction occurs without myofibroblast involvement.[57] Later, fibroblasts, stimulated by growthfactors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, areresponsible for contraction.[57] Myofibroblasts contain the same kind of actin as that found in smooth musclecells.[33]

Myofibroblasts are attracted by fibronectin and growth factors and they move along fibronectin linked to fibrinin the provisional ECM in order to reach the wound edges.[25] They form connections to the ECM at the woundedges, and they attach to each other and to the wound edges by desmosomes. Also, at an adhesion called thefibronexus, actin in the myofibroblast is linked across the cell membrane to molecules in the extracellular matrixlike fibronectin and collagen.[57] Myofibroblasts have many such adhesions, which allow them to pull the ECMwhen they contract, reducing the wound size.[33] In this part of contraction, closure occurs more quickly than inthe first, myofibroblast-independent part.[57]

As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen toreinforce the wound as myofibroblasts contract.[2] The contraction stage in proliferation ends as myofibroblastsstop contracting and commit apoptosis.[33] The breakdown of the provisional matrix leads to a decrease inhyaluronic acid and an increase in chondroitin sulfate, which gradually triggers fibroblasts to stop migrating andproliferating.[19] 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 tohave begun.[20] During maturation, type III collagen, which is prevalent during proliferation, is replaced by typeI collagen.[17] Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tensionlines.[32] The onset of the maturation phase may vary extensively, depending on the size of the wound andwhether it was initially closed or left open,[28] ranging from approximately 3 days[43] to 3 weeks.[58] Thematuration phase can last for a year or longer, similarly depending on wound type.[28]

As the phase progresses, the tensile strength of the wound increases, with the strength approaching 50% that ofnormal tissue by three months after injury and ultimately becoming as much as 80% as strong as normaltissue.[28] Since activity at the wound site is reduced, the scar loses its red appearance as blood vessels that areno longer needed are removed by apoptosis.[20]

The phases of wound healing normally progress in a predictable, timely manner; if they do not, healing mayprogress inappropriately to either a chronic wound [6] such as a venous ulcer or pathological scarring such as akeloid scar.[59][60]

Factors affecting wound healingMany factors controlling the efficacy, speed, and manner of wound healing fall under two types: local andsystemic factors.

Local factorsMechanical factorsEdemaIschemia and necrosisForeign bodiesLow oxygen tension

Systemic factors

Inadequate perfusionInflammationDiabetesNutrientsMetabolic diseasesImmunosuppressionConnective tissue disordersSmoking

Research and developmentUp until a decade ago, the classic paradigm of wound healing, involving stem cells restricted to organ-specificlineages, had never been seriously challenged. Since then, the notion of adult stem cells having cellularplasticity or the ability to differentiate into non-lineage cells has emerged as an alternative explanation.[1] To bemore specific, hematopoietic progenitor cells (that give rise to mature cells in the blood) may have the abilityde-differentiate back into hematopoietic stem cells and/or transdifferentiate into non-lineage cells, such asfibroblasts.[41]

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

It is thought that the epidermis and dermis are reconstituted by mitotically active stem cells that reside at theapex of rete ridges (basal stem cells or BSC), the bulge of hair follicles (hair follicular stem cell or HFSC), andthe papillary dermis (dermal stem cells).[1] Moreover, bone marrow may also contain stem cells that play amajor role in cutaneous wound healing.[41]

In rare circumstances, such as extensive cutaneous injury, self-renewal subpopulations in the bone marrow areinduced to participate in the healing process, whereby they give rise to collagen-secreting cells that seem to playa role during wound repair.[1] These two self-renewal subpopulations are (1) bone marrow-derivedmesenchymal stem cells (MSC) and (2) hematopoietic stem cells (HSC). Bone marrow also harbors aprogenitor subpopulation (endothelial progenitor cells or EPC) that, in the same type of setting, are mobilized toaid in the reconstruction of blood vessels.[41] Moreover, it thought that, extensive injury to skin also promotesthe early trafficking of a unique subclass of leukocytes (circulating fibrocytes) to the injured region, where theyperform various functions related to wound healing.[1]

Wound repair versus regenerationAn injury is an interruption of morphology and/or functionality of a given tissue. After injury, structural tissueheals with incomplete or complete regeneration.[61][62] On the other hand, tissue without an interruption tomorphology almost always completely regenerates. An example of complete regeneration without aninterruption of the morphology is non-injured tissue, such as skin.[63] Non-injured skin has a continuedreplacement and regeneration of cells which always results in complete regeneration.[63]

There is a subtle distinction between 'repair' and regeneration.[1][61][62] Repair means incompleteregeneration.[61] Repair or incomplete regeneration, refers to the physiologic adaptation of an organ after injuryin an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue.[61] Truetissue regeneration or complete regeneration,[62] refers to the replacement of lost/damaged tissue with anexact copy, such that both morphology and functionality are completely restored.[62] Though after injury

mammals can completely regenerate spontaneously, they usually do not completely regenerate. An example of atissue regenerating completely after an interruption of morphology is the endometrium; the endometrium afterthe process of breakdown via the menstruation cycle heals with complete regeneration.[63]

In some instances, after a tissue breakdown, such as in skin, a regeneration closer to complete regeneration maybe induced by the use of biodegradable (collagen-glycoaminoglycan) scaffolds. These scaffolds are structurallyanalogous to extracellular matrix (ECM) found in normal/un-injured dermis.[64] Interestingly, fundamentalconditions required for tissue regeneration often oppose conditions that favor efficient wound repair, includinginhibition of (1) platelet activation, (2) inflammatory response, and (3) wound contraction.[1] In addition toproviding support for fibroblast and endothelial cell attachment, biodegradable scaffolds inhibit woundcontraction, 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 differentiation.[65]

A new way of thinking derived from the notion that heparan sulfates are key player in tissue homeostasis: theprocess that makes the tissue replace dead cells by identical cells. In wound areas, tissue homeostasis is lost asthe heparan sulfates are degraded preventing the replacement of dead cells by identical cells. Heparan sulfateanalogues cannot be degraded by all know heparanases and glycanases and bind to the free heparin sulfatebinding spots on the ECM, therefore preserving the normal tissue homeostasis and preventingscarring.[66][67][68]

Scarless wound healingScarless wound healing is a concept based on the healing or repair of the skin (or other tissue/organs) afterinjury with the aim of healing with subjectively and relatively less scar tissue than normally expected. Scarlesshealing is sometimes mixed up with the concept of scar free healing, which is wound healing which results inabsolutely no scar (free of scarring). However they are different concepts.

A reverse to scarless wound healing is scarification (wound healing to scar more). Historically, certain culturesconsider scarification attractive,[69] however, this is generally not the case in the modern western society, inwhich many patients are turning to plastic surgery clinics with unrealistic expectations. Depending on scar type,treatment may be invasive (intralesional steroid injections, surgery) and/or conservative (compression therapy,topical silicone gel, brachytherapy, photodynamic therapy).[70] Clinical judgment is necessary to successfullybalance the potential benefits of the various treatments available against the likelihood of a poor response andpossible complications resulting from these treatments. Many of these treatments may only have a placeboeffect, and the evidence base for the use of many current treatments is poor.[71]

In the last few decades, comprehension of the basic biologic processes involved in wound repair and tissueregeneration have expanded due to advances in cellular and molecular biology.[72] Currently, the principal goalsin wound management are to achieve rapid wound closure with a functional tissue that has minimal aestheticscaring.[73] However, the ultimate goal of wound healing biology is to induce a more perfect reconstruction ofthe wound area. Scarless wound healing only occurs in mammalian foetal tissues [74] and complete regenerationis limited to lower vertebrates, such as salamanders, and invertebrates.[75] In adult humans, injured tissue arerepaired by collagen deposition, collagen remodelling and eventual scar formation, where fetal wound healing isbelieved to be more of a regenerative process with minimal or no scar formation.[74] Therefore, foetal wound

healing can be used to provide an accessible mammalian model of an optimal healing response in adult humantissues. Clues as to how this might be achieved come from studies of wound healing in embryos, where repair isfast and efficient and results in essentially perfect regeneration of any lost tissue.

The etymology of the term scarless wound healing has a long history.[76][77][78] In print the antiquated conceptof scarless healing was brought up the early 20th century and appeared in a paper published in the LondonLancet. This process involved cutting in a surgical slant, instead of a right angle; it was described in variousNewspapers.[76][77][78]

Simulating wound healing from a growth perspectiveConsiderable effort has been devoted to understanding the physical relationships governing wound healing andsubsequent scarring, with mathematical models and simulations developed to elucidate these relationships.[79]The growth of tissue around the wound site is a result of the migration of cells and collagen deposition by thesecells. The alignment of collagen describes the degree of scarring; basket-weave orientation of collagen ischaracteristic of normal skin, whereas aligned collagen fibers lead to significant scarring.[80] It has been shownthat the growth of tissue and extent of scar formation can be controlled by modulating the stress at a woundsite.[81]

The growth of tissue can be simulated using the aforementioned relationships from a biochemical andbiomechanical point of view. The biologically active chemicals that play an important role in wound healing aremodeled with Fickian diffusion to generate concentration profiles. The balance equation for open systems whenmodeling wound healing incorporates mass growth due to cell migration and proliferation. Here the followingequation is used:

Dt0 = Div (R) + R0,

where represents mass density, R represents a mass flux (from cell migration), and R0 represents a masssource (from cell proliferation, division, or enlargement).[82]

Wound closure intentionsPrimary intention

When wound edges are brought together (sutured/glued) so that they are adjacent to each other (re-approximated)Minimizes scarringMost surgical wounds heal by primary intention healingWound closure is performed with sutures (stitches), staples, or adhesive tape or glue.Examples: well-repaired lacerations, well reduced bone fractures, healing after flap surgery

Secondary intention

The wound is allowed to granulateSurgeon may pack the wound with a gauze or use a drainage systemGranulation results in a broader scarHealing process can be slow due to presence of drainage from infectionWound care must be performed daily to encourage wound debris removal to allow for granulation tissueformationExamples: gingivectomy, gingivoplasty, tooth extraction sockets, poorly reduced fractures, burns, severelacerations, pressure ulcers

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 openExamples: healing of wounds by use of tissue grafts.

If the wound edges are not reapproximated immediately, delayed primary wound healing transpires. This typeof healing may be desired in the case of contaminated wounds. By the fourth day, phagocytosis of contaminatedtissues 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 areencircled by mononuclear leukocytes, forming granulomas. Usually the wound is closed surgically at thisjuncture, and if the "cleansing" of the wound is incomplete, chronic inflammation can ensue, resulting inprominent scarring.

Overview of involved growth factorsFollowing are the main growth factors involved in wound healing:

Growth factor Abbreviation Main origins Effects

Epidermal growthfactor EGF

ActivatedmacrophagesSalivaryglandsKeratinocytes

Keratinocyte and fibroblast mitogenKeratinocyte migrationGranulation tissue formation

Transforminggrowth factor- TGF-

ActivatedmacrophagesT-

Hepatocyte and epithelial cell proliferationExpression of antimicrobial peptides

lymphocytesKeratinocytes

Expression of chemotactic cytokines

Hepatocyte growthfactor HGF

Mesenchymalcells

Epithelial and endothelial cell proliferationHepatocyte motility

Vascular endothelialgrowth factor VEGF

Mesenchymalcells

Vascular permeabilityEndothelial cell proliferation

Platelet derivedgrowth factor PDGF

PlateletsMacrophagesEndothelialcellsSmoothmuscle cellsKeratinocytes

Granulocyte, macrophage, fibroblast andsmooth muscle cell chemotaxisGranulocyte, macrophage and fibroblastactivationFibroblast, endothelial cell and smoothmuscle cell proliferationMatrix metalloproteinase, fibronectin andhyaluronan productionAngiogenesisWound remodelingIntegrin expression regulation

Fibroblast growthfactor 1 and 2 FGF-1, 2

MacrophagesMast cellsT-lymphocytesEndothelialcellsFibroblasts

Fibroblast chemotaxisFibroblast and keratinocyte proliferationKeratinocyte migrationAngiogenesisWound contractionMatrix (collagen fibers) deposition

PlateletsT-lymphocytesMacrophages

Granulocyte, macrophage, lymphocyte,fibroblast and smooth muscle cellchemotaxisTIMP synthesis

Transforminggrowth factor-

TGF- EndothelialcellsKeratinocytesSmoothmuscle cellsFibroblasts

AngiogenesisFibroplasiaMatrix metalloproteinase productioninhibitionKeratinocyte proliferation

Keratinocyte growthfactor KGF Keratinocytes

Keratinocyte migration, proliferation anddifferentiation

Unless else specified in boxes, then reference is:[83]

Complications of Wound HealingThe major complications are many:

1. Deficient Scar Formation: Result in wound dehiscence or rupture of the wound due to inadequateformation of granulation tissue.

2. Excessive Scar Formation: Hypertrophic scar, Keloid, Desmoid.3. Exuberant Granulation (Proud flesh).4. Deficient Contraction (in skin grafts) or excessive contraction (in burns).5. Others: Dystrophic calcification, pigmentary changes, painful scars, inscisional hernia etc.

See alsoDressing (medical)History of wound careWound bed preparation

Notes and references1. ^ a b c d e f g h i j k Nguyen, D.T., Orgill D.P., Murphy G.F. (2009). Chapter 4: The Pathophysiologic Basis for Wound

Healing and Cutaneous Regeneration (http://books.google.com/books?hl=en&lr=&id=-6yjAgAAQBAJ&oi=fnd&pg=PA25&dq=nguyen+orgill+murphy&ots=qCXn0n06DS&sig=xp-U3skWHLzXuxKByg6neNJh5hk#v=onepage&q=nguyen%20orgill%20murphy&f=false). Biomaterials For TreatingSkin Loss (http://www.docin.com/p-109651173.html). Woodhead Publishing (UK/Europe) & CRC Press (US),Cambridge/Boca Raton, p. 25-57. (ISBN 978-1-4200-9989-8/ISBN 978-1-84569-363-3)

2. ^ a b c d e f g h i j k l m Stadelmann, WK; Digenis, AG; Tobin, GR (1998). "Physiology and healing dynamics of chroniccutaneous wounds". American journal of surgery 176 (2A Suppl): 26S38S. doi:10.1016/S0002-9610(98)00183-4(https://dx.doi.org/10.1016%2FS0002-9610%2898%2900183-4). PMID 9777970(https://www.ncbi.nlm.nih.gov/pubmed/9777970).

3. ^ Quinn, J.V. (1998). Tissue Adhesives in Wound Care. Hamilton, Ont. B.C. Decker, Inc. Electronic book.4. ^ Rasche, H (2001). "Haemostasis and thrombosis: an overview"

(http://eurheartjsupp.oxfordjournals.org/content/3/suppl_Q/Q3.abstract). European Heart Journal Supplements 3(Supplement Q): Q3Q7. doi:10.1016/S1520-765X(01)90034-3 (https://dx.doi.org/10.1016%2FS1520-765X%2801%2990034-3).

5. ^ Versteeg, H. H.; Heemskerk, J. W. M.; Levi, M.; Reitsma, P. H. (9 January 2013). "New Fundamentals in Hemostasis"(http://physrev.physiology.org/content/93/1/327.figures-only). Physiological Reviews 93 (1): 327358.doi:10.1152/physrev.00016.2011 (https://dx.doi.org/10.1152%2Fphysrev.00016.2011).

6. ^ a b c d e f g h Midwood, K.S.; Williams, L.V.; Schwarzbauer, J.E. (2004). "Tissue repair and the dynamics of theextracellular matrix". The International Journal of Biochemistry & Cell Biology 36 (6): 10311037.doi:10.1016/j.biocel.2003.12.003 (https://dx.doi.org/10.1016%2Fj.biocel.2003.12.003). PMID 15094118(https://www.ncbi.nlm.nih.gov/pubmed/15094118).

7. ^ Chang, HY; Sneddon, JB; Alizadeh, AA; Sood, R; West, RB; Montgomery, K; Chi, JT; Van De Rijn, M et al. (2004)."Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumorsand wounds" (http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020007).PLoS Biology 2 (2): E7. doi:10.1371/journal.pbio.0020007 (https://dx.doi.org/10.1371%2Fjournal.pbio.0020007).PMC 314300 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC314300). PMID 14737219(https://www.ncbi.nlm.nih.gov/pubmed/14737219).

8. ^ Garg, H.G. (2000). Scarless Wound Healing. New York Marcel Dekker, Inc. Electronic book.9. ^ Enoch, S. Price, P. (2004). Cellular, molecular and biochemical differences in the pathophysiology of healing between

acute wounds, chronic wounds and wounds in the elderly.http://www.worldwidewounds.com/2004/august/Enoch/Pathophysiology-Of-Healing.html

10. ^ Reference list is found on image main page.11. ^ Galko MJ, Krasnow MA (2004). "Cellular and genetic analysis of wound healing in Drosophila Larvae"

(http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020239). PLoS Biology 2(8): e239. doi:10.1371/journal.pbio.0020239 (https://dx.doi.org/10.1371%2Fjournal.pbio.0020239). PMC 479041(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC479041). PMID 15269788(https://www.ncbi.nlm.nih.gov/pubmed/15269788).

12. ^ Cubison TC, Pape SA, Parkhouse N (December 2006). "Evidence for the link between healing time and thedevelopment of hypertrophic scars (HTS) in paediatric burns due to scald injury". Burns 32 (8): 9929.doi:10.1016/j.burns.2006.02.007 (https://dx.doi.org/10.1016%2Fj.burns.2006.02.007). PMID 16901651(https://www.ncbi.nlm.nih.gov/pubmed/16901651).

13. ^ John Kraft and Charles Lynde, MD, FRCPC. "Giving Burns the First, Second and Third Degree - Classification ofburns" (http://www.skincareguide.ca/articles/general_skin_care/gen_skin_care_art_3.html). skincareguide.ca. Retrieved31 January 2012. "Formation of a thick eschar, slow healing (>1month), Obvious scarring,"

14. ^ a b "POST BURN SCAR RELATIVE TO RE-EPITHELIALIZATION"(http://web.archive.org/web/20120425052018/http://www.burnsurgery.com/Modules/BurnWound%201/sect_IX.htm).Burnsurgery.org. 2011. Archived from the original(http://www.burnsurgery.com/Modules/BurnWound%201/sect_IX.htm) on 25 April 2014. Retrieved 16 March 2011."Healing in 2 weeks minimal to no scar; Healing in 3 weeks minimal to no scar except in high risk scarformers;Healing in 4 weeks or more hypertrophic in more than 50% of patients"

15. ^ a b c d e Rosenberg L., de la Torre J. (2006). Wound Healing, Growth Factors(http://www.emedicine.com/plastic/topic457.htm). Emedicine.com. Accessed January 20, 2008.

16. ^ Sandeman, S.R.; Allen, M.C.; Liu, C.; Faragher, R.G.A.; Lloyd, A.W. (2000). "Human keratocyte migration intocollagen gels declines with in vitro ageing". Mechanisms of Ageing and Development 119 (3): 149157.doi:10.1016/S0047-6374(00)00177-9 (https://dx.doi.org/10.1016%2FS0047-6374%2800%2900177-9). PMID 11080534(https://www.ncbi.nlm.nih.gov/pubmed/11080534).

17. ^ a b c d Dealey C. (1999). The care of wounds: A guide for nurses. Oxford ; Malden, Mass. Blackwell Science.Electronic book.

18. ^ Theoret, C.L. (2004). "Update on wound repair". Clinical Techniques in Equine Practice 3 (2): 110122.doi:10.1053/j.ctep.2004.08.009 (https://dx.doi.org/10.1053%2Fj.ctep.2004.08.009).

19. ^ a b c d e f g h de la Torre J., Sholar A. (2006). Wound healing: Chronic wounds(http://www.emedicine.com/plastic/topic477.htm). Emedicine.com. Accessed January 20, 2008.

20. ^ a b c d e f g h Greenhalgh, D.G. (1998). "The role of apoptosis in wound healing". The International Journal ofBiochemistry & Cell Biology 30 (9): 10191030. doi:10.1016/S1357-2725(98)00058-2(https://dx.doi.org/10.1016%2FS1357-2725%2898%2900058-2). PMID 9785465(https://www.ncbi.nlm.nih.gov/pubmed/9785465).

21. ^ Muller, M.J.; Hollyoak, M.A.; Moaveni, Z.; La, T.; Brown, H.; Herndon, D.N.; Heggers, J.P. (2003). "Retardation ofwound healing by silver sulfadiazine is reversed by Aloe vera and nystatin". Burns 29 (8): 834836. doi:10.1016/S0305-4179(03)00198-0 (https://dx.doi.org/10.1016%2FS0305-4179%2803%2900198-0). PMID 14636760(https://www.ncbi.nlm.nih.gov/pubmed/14636760).

22. ^ Martin, P.; Leibovich, SJ (2005). "Inflammatory cells during wound repair: the good, the bad and the ugly". Trends inCell Biology 15 (11): 599607. doi:10.1016/j.tcb.2005.09.002 (https://dx.doi.org/10.1016%2Fj.tcb.2005.09.002).PMID 16202600 (https://www.ncbi.nlm.nih.gov/pubmed/16202600).

23. ^ a b c d e f g h Santoro, M.M.; Gaudino, G. (2005). "Cellular and molecular facets of keratinocyte reepithelization duringwound healing". Experimental Cell Research 304 (1): 274286. doi:10.1016/j.yexcr.2004.10.033(https://dx.doi.org/10.1016%2Fj.yexcr.2004.10.033). PMID 15707592(https://www.ncbi.nlm.nih.gov/pubmed/15707592).

24. ^ a b Expert Reviews in Molecular Medicine. (2003). The phases of cutaneous wound healing (http://www-ermm.cbcu.cam.ac.uk/03005829a.pdf). 5: 1. Cambridge University Press. Accessed January 20, 2008.

25. ^ a b c d e f Deodhar, AK; Rana, RE (4/1/1997). "Surgical physiology of wound healing: a review"(http://www.jpgmonline.com/article.asp?issn=0022-3859;year=1997;volume=43;issue=2;spage=52;epage=6;aulast=Deodhar). Journal of Postgraduate Medicine 43 (2): 526. PMID 10740722 (https://www.ncbi.nlm.nih.gov/pubmed/10740722). Check date values in: |date= (help)

26. ^ Ovchinnikov, Dmitry A. (2008). "Macrophages in the embryo and beyond: Much more than just giant phagocytes"(http://www.researchgate.net/publication/227897252_Macrophages_in_the_embryo_and_beyond_Much_more_than_just_giant_phagocytes). Genesis (Institute for Molecular Bioscience and Cooperative Research Centre for ChronicInflammatory Diseases (CRC-CID), University of Queensland, Brisbane, Queensland, Australia.: researchgate.net) 46(9): 44762. doi:10.1002/dvg.20417 (https://dx.doi.org/10.1002%2Fdvg.20417). PMID 18781633(https://www.ncbi.nlm.nih.gov/pubmed/18781633). Retrieved 2013-06-28. "Macrophages are present essentially in alltissues, beginning with embryonic development and, in addition to their role in host defense and in the clearance ofapoptotic cells, are being increasingly recognized for their trophic function and role in regeneration."

27. ^ a b c d Newton, P. M.; Watson, J. A.; Wolowacz, R. G.; Wood, E. J. (2004). "Macrophages Restrain Contraction of anIn Vitro Wound Healing Model" (http://www.springerlink.com/content/g518380278431706/). Inflammation 28 (4): 20714. doi:10.1023/B:IFLA.0000049045.41784.59 (https://dx.doi.org/10.1023%2FB%3AIFLA.0000049045.41784.59).PMID 15673162 (https://www.ncbi.nlm.nih.gov/pubmed/15673162).

28. ^ a b c d e f g h Mercandetti M., Cohen A.J. (2005). Wound Healing: Healing and Repair(http://www.emedicine.com/plastic/topic411.htm). Emedicine.com. Accessed January 20, 2008.

29. ^ Stashak, T.S.; Farstvedt, E.; Othic, A. (2004). "Update on wound dressings: Indications and best use". ClinicalTechniques in Equine Practice 3 (2): 148163. doi:10.1053/j.ctep.2004.08.006(https://dx.doi.org/10.1053%2Fj.ctep.2004.08.006).

30. ^ Swirski, F. K.; Nahrendorf, M.; Etzrodt, M.; Wildgruber, M.; Cortez-Retamozo, V.; Panizzi, P.; Figueiredo, J.-L.;Kohler, R. H. et al. (2009). "Identification of Splenic Reservoir Monocytes and Their Deployment to Inflammatory Sites"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803111). Science 325 (5940): 612616. Bibcode:2009Sci...325..612S(http://adsabs.harvard.edu/abs/2009Sci...325..612S). doi:10.1126/science.1175202(https://dx.doi.org/10.1126%2Fscience.1175202). PMC 2803111(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803111). PMID 19644120(https://www.ncbi.nlm.nih.gov/pubmed/19644120).

31. ^ Jia, T.; Pamer, E. G. (2009). "Dispensable But Not Irrelevant"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917045). Science 325 (5940): 549550. Bibcode:2009Sci...325..549J(http://adsabs.harvard.edu/abs/2009Sci...325..549J). doi:10.1126/science.1178329(https://dx.doi.org/10.1126%2Fscience.1178329). PMC 2917045(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2917045). PMID 19644100(https://www.ncbi.nlm.nih.gov/pubmed/19644100).

32. ^ a b c d e f g h i Lorenz H.P. and Longaker M.T. (2003). Wounds: Biology, Pathology, and Management(http://recon.stanford.edu/Articles/LorenzWH.pdf). Stanford University Medical Center. Accessed January 20, 2008.

33. ^ a b c d e Hinz, B (2006). "Masters and servants of the force: the role of matrix adhesions in myofibroblast forceperception and transmission". European Journal of Cell Biology 85 (34): 17581. doi:10.1016/j.ejcb.2005.09.004(https://dx.doi.org/10.1016%2Fj.ejcb.2005.09.004). PMID 16546559 (https://www.ncbi.nlm.nih.gov/pubmed/16546559).

34. ^ Souppouris, Aaron (2013-05-23). "Scientists identify cell that could hold the secret to limb regeneration"(http://www.theverge.com/2013/5/23/4358418/salamander-macrophages-could-aid-limb-regeneration). the verge.com."Researchers have identified a cell that aids limb regrowth in Salamanders. Macrophages are a type of repairing cell thatdevour dead cells and pathogens, and trigger other immune cells to respond to pathogens."

35. ^ James W. Godwin, Alexander R. Pinto, and Nadia A. Rosenthal (2013-04-24). "Macrophages are required for adultsalamander limb regeneration" (http://www.pnas.org/content/early/2013/05/17/1300290110). University of Texas.

36. ^ a b c d Falanga V. (2005). Wound Healing. American Academy of Dermatology (AAD).37. ^ Birbrair, A.; Zhang, T.; Wang, Z.-M.; Messi, M. L.; Olson, J. D.; Mintz, A.; Delbono, O. (2014). "Type-2 pericytes

participate in normal and tumoral angiogenesis". AJP: Cell Physiology 307 (1): C25. doi:10.1152/ajpcell.00171.2013(https://dx.doi.org/10.1152%2Fajpcell.00171.2013).

38. ^ a b c Kuwahara R.T. and Rasberry R. 2007. Chemical Peels (http://www.emedicine.com/derm/topic533.htm).Emedicine.com. Accessed September 15, 2007.

39. ^ a b c d e f g h i j Romo T. and Pearson J.M. 2005. Wound Healing, Skin (http://www.emedicine.com/ent/topic13.htm).Emedicine.com. Accessed December 27, 2006.

40. ^ Lansdown, A.B.G.; Sampson, B.; Rowe, A. (2001). "Experimental observations in the rat on the influence of cadmiumon skin wound repair" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517695). International Journal ofExperimental Pathology 82 (1): 3541. doi:10.1046/j.1365-2613.2001.00180.x (https://dx.doi.org/10.1046%2Fj.1365-2613.2001.00180.x). PMC 2517695 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2517695). PMID 11422539(https://www.ncbi.nlm.nih.gov/pubmed/11422539).

41. ^ a b c d Song, G; Nguyen, DT; Pietramaggiori, G; Scherer, S; Chen, B; Zhan, Q; Ogawa, R; Yannas, IV et al. (2010)."Use of the parabiotic model in studies of cutaneous wound healing to define the participation of circulating cells"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935287). Wound Repair and Regeneration 18 (4): 426432.doi:10.1111/j.1524-475X.2010.00595.x (https://dx.doi.org/10.1111%2Fj.1524-475X.2010.00595.x). PMC 2935287(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935287). PMID 20546556(https://www.ncbi.nlm.nih.gov/pubmed/20546556).

42. ^ Ruszczak, Z. (2003). "Effect of collagen matrices on dermal wound healing". Advanced Drug Delivery Reviews 55(12): 15951611. doi:10.1016/j.addr.2003.08.003 (https://dx.doi.org/10.1016%2Fj.addr.2003.08.003). PMID 14623403(https://www.ncbi.nlm.nih.gov/pubmed/14623403).

43. ^ a b Fig. 9-1. The cellular, biochemical, and mechanical phases of wound healing. Pollock, Raphael E.; F. CharlesBrunicardi; Dana K. Andersen; Billiar, Timothy R.; Dunn, David; Hunter, John G.; Matthews, Jeffrey J. (2009).Schwartz's Principles of Surgery, Ninth Edition. McGraw-Hill Professional. ISBN 0-07-154769-X.

44. ^ a b c d e f g h DiPietro L.A. and Burns A.L., Eds. 2003. Wound Healing: Methods and Protocols. Methods in MolecularMedicine. Totowa, N.J. Humana Press. Electronic book.

45. ^ Fu XB, Sun TZ, Li XK, Sheng ZY (February 2005). "Morphological and distribution characteristics of sweat glands inhypertrophic scar and their possible effects on sweat gland regeneration" (http://www.cmj.org/Periodical/LinkIn.asp?journal=Chinese%20Medical%20Journal&linkintype=pubmed&year=2005&vol=118&issue=3&beginpage=186).Chinese Medical Journal 118 (3): 18691. PMID 15740645 (https://www.ncbi.nlm.nih.gov/pubmed/15740645).

46. ^ a b "BURN INJURIES" (http://www.nationaltraumainstitute.org/home/burn_injuries.html). nationaltraumainstitute.org.Retrieved 18-03-18. "When the dermis is destroyed, the scars do not regrow hair, nerves or sweat glands, providingadditional challenges to body temperature control." Check date values in: |accessdate= (help)

47. ^ a b c d Bartkova, Jirina; Grn, Birgitte; Dabelsteen, Erik; Bartek, Jiri (2003). "Cell-cycle regulatory proteins in humanwound healing". Archives of Oral Biology 48 (2): 12532. doi:10.1016/S0003-9969(02)00202-9(https://dx.doi.org/10.1016%2FS0003-9969%2802%2900202-9). PMID 12642231(https://www.ncbi.nlm.nih.gov/pubmed/12642231).

48. ^ a b c d Mulvaney M. and Harrington A. 1994. Chapter 7: Cutaneous trauma and its treatment(http://web.archive.org/web/20031218072356/http://www.vnh.org/MilitaryDerm/Ch7.pdf). In, Textbook of MilitaryMedicine: Military Dermatology. Office of the Surgeon General, Department of the Army. Virtual Naval HospitalProject. Accessed through web archive on September 15, 2007.

49. ^ a b c d Larjava H., Koivisto L., and Hakkinen L. 2002. Chapter 3: Keratinocyte Interactions with Fibronectin DuringWound Healing. In, Heino, J. and Kahari, V.M. Cell Invasion. Medical Intelligence Unit ; 33. Georgetown, Tex., Austin,Tex Landes Bioscience, Inc. Electronic book.

50. ^ Witte, Maria B; Barbul, Adrian (2002). "Role of nitric oxide in wound repair". The American Journal of Surgery 183(4): 40612. doi:10.1016/S0002-9610(02)00815-2 (https://dx.doi.org/10.1016%2FS0002-9610%2802%2900815-2).PMID 11975928 (https://www.ncbi.nlm.nih.gov/pubmed/11975928).

51. ^ Son, Hyun Joo; Bae, Hyun Chul; Kim, Hyun Jeong; Lee, Dong Hee; Han, Dong-Wook; Park, Jong-Chul (2005)."Effects of -glucan on proliferation and migration of fibroblasts". Current Applied Physics 5 (5): 46871.Bibcode:2005CAP.....5..468S (http://adsabs.harvard.edu/abs/2005CAP.....5..468S). doi:10.1016/j.cap.2005.01.011(https://dx.doi.org/10.1016%2Fj.cap.2005.01.011).

52. ^ Falanga, Vincent (2004). "The chronic wound: Impaired healing and solutions in the context of wound bedpreparation". Blood Cells, Molecules, and Diseases 32 (1): 8894. doi:10.1016/j.bcmd.2003.09.020(https://dx.doi.org/10.1016%2Fj.bcmd.2003.09.020). PMID 14757419(https://www.ncbi.nlm.nih.gov/pubmed/14757419).

53. ^ Etscheid, M.; Beer, N.; Dodt, J. (2005). "The hyaluronan-binding protease upregulates ERK1/2 and PI3K/Aktsignalling pathways in fibroblasts and stimulates cell proliferation and migration". Cellular Signalling 17 (12): 148694.doi:10.1016/j.cellsig.2005.03.007 (https://dx.doi.org/10.1016%2Fj.cellsig.2005.03.007). PMID 16153533(https://www.ncbi.nlm.nih.gov/pubmed/16153533).

54. ^ Bayram, Yalcin; Deveci, Mustafa; Imirzalioglu, Nejat; Soysal, Yasemin; Sengezer, Mustafa (2005). "The cell baseddressing with living allogenic keratinocytes in the treatment of foot ulcers: A case study". British Journal of PlasticSurgery 58 (7): 98896. doi:10.1016/j.bjps.2005.04.031 (https://dx.doi.org/10.1016%2Fj.bjps.2005.04.031).PMID 16040019 (https://www.ncbi.nlm.nih.gov/pubmed/16040019).

55. ^ Grinnell, F. (1994). "Fibroblasts, myofibroblasts, and wound contraction"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2119916). J. Cell Biol 124 (4): 401404. doi:10.1083/jcb.124.4.401(https://dx.doi.org/10.1083%2Fjcb.124.4.401). PMC 2119916(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2119916). PMID 8106541(https://www.ncbi.nlm.nih.gov/pubmed/8106541).

56. ^ a b Eichler, MJ; Carlson, MA (2006). "Modeling dermal granulation tissue with the linear fibroblast-populated collagenmatrix: a comparison with the round matrix model". Journal of dermatological science 41 (2): 97108.doi:10.1016/j.jdermsci.2005.09.002 (https://dx.doi.org/10.1016%2Fj.jdermsci.2005.09.002). PMID 16226016(https://www.ncbi.nlm.nih.gov/pubmed/16226016).

57. ^ a b c d Mirastschijski, U.; Haaksma, C.J.; Tomasek, J.J.; gren, M.S. (2004). "Matrix metalloproteinase inhibitor GM6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds". Experimental CellResearch 299 (2): 465475. doi:10.1016/j.yexcr.2004.06.007 (https://dx.doi.org/10.1016%2Fj.yexcr.2004.06.007).PMID 15350544 (https://www.ncbi.nlm.nih.gov/pubmed/15350544).

58. ^ worldwidewounds.com (http://www.worldwidewounds.com/2005/august/Schultz/Extrace-Matric-Acute-Chronic-Wounds.html) > Figure 3 The time relationship between the different processes of wound healing.(http://www.worldwidewounds.com/2005/august/Schultz/images/New_fig_3.jpg) by Gregory S Schultz, Glenn Ladwigand Annette Wysocki in turn adapted from Asmussen PD, Sollner B. Mechanism of wound healing. In: Wound Care.Tutorial Medical Series. Stuttgart: Hippokrates Verlag, 1993.

59. ^ O'Leary, R; Wood, EJ; Guillou, PJ (2002). "Pathological scarring: Strategic interventions". The European journal ofsurgery 168 (10): 52334. PMID 12666691 (https://www.ncbi.nlm.nih.gov/pubmed/12666691).

60. ^ Desmoulire, Alexis; Chaponnier, Christine; Gabbiani, Giulio (2005). "Tissue repair, contraction, and themyofibroblast". Wound Repair and Regeneration 13 (1): 712. doi:10.1111/j.1067-1927.2005.130102.x(https://dx.doi.org/10.1111%2Fj.1067-1927.2005.130102.x). PMID 15659031(https://www.ncbi.nlm.nih.gov/pubmed/15659031).

61. ^ a b c d Min, Su; Wang, Song W.; Orr, William (2006). "Graphic general pathology: 2.3 Incomplete regeneration:"(http://pathol.med.stu.edu.cn/pathol/listEngContent2.aspx?contentID=493). Pathology. pathol.med.stu.edu.cn. Retrieved2012-12-07. "The new tissue is not the same as the tissue that was lost. After the repair process has been completed,there is a loss in the structure or function of the injured tissue. In this type of repair, it is common that granulation tissue(stromal connective tissue) proliferates to fill the defect created by the necrotic cells. The necrotic cells are then replacedby scar tissue."

62. ^ a b c d Min, Su; Wang, Song W.; Orr, William (2006). "Graphic general pathology: 2.2 complete regeneration:"(http://pathol.med.stu.edu.cn/pathol/listEngContent2.aspx?ContentID=492). Pathology. pathol.med.stu.edu.cn. Retrieved2012-12-07. "(1) Complete regeneration: The new tissue is the same as the tissue that was lost. After the repair processhas been completed, the structure and function of the injured tissue are completely normal"

63. ^ a b c Min, Su; Wang, Song W.; Orr, William (2006). "Graphic general pathology: 2.2 complete regeneration:"(http://pathol.med.stu.edu.cn/pathol/listEngContent2.aspx?ContentID=492). Pathology. pathol.med.stu.edu.cn. Retrieved2013-11-10. "After the repair process has been completed, the structure and function of the injured tissue are completelynormal. This type of regeneration is common in physiological situations. Examples of physiological regeneration are thecontinual replacement of cells of the skin and repair of the endometrium after menstruation. Complete regeneration canoccur in pathological situations in tissues that have good regenerative capacity."

64. ^ Yannas, I. V.; Lee, E; Orgill, DP; Skrabut, EM; Murphy, GF (1989). "Synthesis and Characterization of a ModelExtracellular Matrix that Induces Partial Regeneration of Adult Mammalian Skin"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC286593). Proceedings of the National Academy of Sciences 86 (3):9337. Bibcode:1989PNAS...86..933Y (http://adsabs.harvard.edu/abs/1989PNAS...86..933Y).doi:10.1073/pnas.86.3.933 (https://dx.doi.org/10.1073%2Fpnas.86.3.933). JSTOR 33315(https://www.jstor.org/stable/33315). PMC 286593 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC286593).PMID 2915988 (https://www.ncbi.nlm.nih.gov/pubmed/2915988).

65. ^ O'Leary, R.; Ponnambalam, S.; Wood, E.J. (2003). "Pioglitazone-induced myofibroblast cell death: Implications forcutaneous scarring". British Journal of Dermatology 149 (3): 6657. doi:10.1046/j.1365-2133.2003.05501.x(https://dx.doi.org/10.1046%2Fj.1365-2133.2003.05501.x). PMID 14511015(https://www.ncbi.nlm.nih.gov/pubmed/14511015).

66. ^ Tong, Miao; Tuk, Bastiaan; Hekking, Ineke M.; Vermeij, Marcel; Barritault, Denis; Van Neck, Johan W. (2009)."Stimulated neovascularization, inflammation resolution and collagen maturation in healing rat cutaneous wounds by aheparan sulfate glycosaminoglycan mimetic, OTR4120". Wound Repair and Regeneration 17 (6): 84052.doi:10.1111/j.1524-475X.2009.00548.x (https://dx.doi.org/10.1111%2Fj.1524-475X.2009.00548.x). PMID 19903305(https://www.ncbi.nlm.nih.gov/pubmed/19903305).

67. ^ Barritault, D.; Caruelle, J.-P. (2006). "Les agents de rgnration (ou RGTAs) : Une nouvelle approche thrapeutique"[Regenerating agents (RGTAs): a new therapeutic approach]. Annales Pharmaceutiques Franaises (in French) 64 (2):13544. doi:10.1016/S0003-4509(06)75306-8 (https://dx.doi.org/10.1016%2FS0003-4509%2806%2975306-8).PMID 16568015 (https://www.ncbi.nlm.nih.gov/pubmed/16568015).

68. ^ Van Neck et al, Heparan sulfate proteoglycan mimetics thrive tissue regeneration: an overview. In Intech book underthe working title "Tissue Regeneration", ISBN 978-953-307-876-2 is scheduled for on line publication on Nov 26, 2011"

69. ^ Rush, J. (2005). Spiritual tattoo: a cultural history of tattooing, piercing, scarification, branding, and implants, FrogLtd.

70. ^ Brown BC, McKenna SP, Siddhi K, McGrouther DA, Bayat A; McKenna; Siddhi; McGrouther; Bayat (September2008). "The hidden cost of skin scars: quality of life after skin scarring". Journal of Plastic, Reconstructive & AestheticSurgery 61 (9): 104958. doi:10.1016/j.bjps.2008.03.020 (https://dx.doi.org/10.1016%2Fj.bjps.2008.03.020).PMID 18617450 (https://www.ncbi.nlm.nih.gov/pubmed/18617450).

71. ^ Bayat A, McGrouther DA, Ferguson MW; McGrouther; Ferguson (January 2003). "Skin scarring"(http://www.bmj.com/cgi/pmidlookup?view=long&pmid=12521975). BMJ 326 (7380): 8892.doi:10.1136/bmj.326.7380.88 (https://dx.doi.org/10.1136%2Fbmj.326.7380.88). PMC 1125033(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1125033). PMID 12521975(https://www.ncbi.nlm.nih.gov/pubmed/12521975).

72. ^ Clark, R. (1996). The molecular and cellular biology of wound repair, Springer Us.73. ^ Tonnesen MG, Feng X, Clark RA; Feng; Clark (December 2000). "Angiogenesis in wound healing". The Journal of

Investigative Dermatology 5 (1): 406. doi:10.1046/j.1087-0024.2000.00014.x (https://dx.doi.org/10.1046%2Fj.1087-0024.2000.00014.x). PMID 11147674 (https://www.ncbi.nlm.nih.gov/pubmed/11147674).

74. ^ a b Ferguson MW, Whitby DJ, Shah M, Armstrong J, Siebert JW, Longaker MT; Whitby; Shah; Armstrong; Siebert;Longaker (April 1996). "Scar formation: the spectral nature of fetal and adult wound repair"(http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0032-1052&volume=97&issue=4&spage=854). Plastic and Reconstructive Surgery 97 (4): 85460. doi:10.1097/00006534-199604000-00029 (https://dx.doi.org/10.1097%2F00006534-199604000-00029). PMID 8628785(https://www.ncbi.nlm.nih.gov/pubmed/8628785).

75. ^ Brockes JP, Kumar A, Velloso CP; Kumar; Velloso (2001). "Regeneration as an evolutionary variable"(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594962). Journal of Anatomy 199 (Pt 12): 311. doi:10.1046/j.1469-7580.2001.19910003.x (https://dx.doi.org/10.1046%2Fj.1469-7580.2001.19910003.x). PMC 1594962(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594962). PMID 11523827(https://www.ncbi.nlm.nih.gov/pubmed/11523827).

76. ^ a b "Scarless Healing" (http://paperspast.natlib.govt.nz/cgi-bin/paperspast?a=d&d=TS19060707.2.27&e=-------10-PubMetaTS-231-byDA---0elmwood--). Star (Christchurch, New Zealand: Star). 1906-07-07. pp. Page 4. Retrieved2013-07-02.

Wikimedia Commons hasmedia related to Woundhealing.

77. ^ a b "Scarless Healing" (http://paperspast.natlib.govt.nz/cgi-bin/paperspast?a=d&d=MEX19060712.2.8). MarlboroughExpress, Volume XXXIX, Issue 160, (paperspast.natlib.govt.nz). 1906-07-12. pp. Page 1. Retrieved 2013-07-02.

78. ^ a b "A Wonderful New Surgery" (http://news.google.com/newspapers?id=DIctAAAAIBAJ&sjid=XJwFAAAAIBAJ&pg=4204,3012981&dq=scarless+healing&hl=en). Reading Eagle. 1906-07-06. pp. Page 6. Retrieved 2013-07-02.

79. ^ Cumming, B. D.; McElwain, D. L. S.; Upton, Z. (2009). "A mathematical model of wound healing and subsequentscarring" (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839370). Journal of the Royal Society Interface 7 (42): 1934. doi:10.1098/rsif.2008.0536 (https://dx.doi.org/10.1098%2Frsif.2008.0536). PMC 2839370(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2839370). PMID 19324672(https://www.ncbi.nlm.nih.gov/pubmed/19324672).

80. ^ Gurtner, Geoffrey C.; Werner, Sabine; Barrandon, Yann; Longaker, Michael T. (2008). "Wound repair andregeneration". Nature 453 (7193): 31421. Bibcode:2008Natur.453..314G(http://adsabs.harvard.edu/abs/2008Natur.453..314G). doi:10.1038/nature07039(https://dx.doi.org/10.1038%2Fnature07039). PMID 18480812 (https://www.ncbi.nlm.nih.gov/pubmed/18480812).

81. ^ Gurtner, Geoffrey C.; Dauskardt, Reinhold H.; Wong, Victor W.; Bhatt, Kirit A.; Wu, Kenneth; Vial, Ivan N.; Padois,Karine; Korman, Joshua M.; Longaker, Michael T. (2011). "Improving Cutaneous Scar Formation by Controlling theMechanical Environment". Annals of Surgery 254 (2): 21725. doi:10.1097/SLA.0b013e318220b159(https://dx.doi.org/10.1097%2FSLA.0b013e318220b159). PMID 21606834(https://www.ncbi.nlm.nih.gov/pubmed/21606834).

82. ^ Kuhl, E.; Steinmann, P. (2004). "Computational modeling of healing: An application of the material force method".Biomechanics and Modeling in Mechanobiology 2 (4): 187203. doi:10.1007/s10237-003-0034-3(https://dx.doi.org/10.1007%2Fs10237-003-0034-3). PMID 14872320(https://www.ncbi.nlm.nih.gov/pubmed/14872320).

83. ^ Table 3-1 in: Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson (2007). Robbins BasicPathology. Philadelphia: Saunders. ISBN 1-4160-2973-7. 8th edition.

External linksWound Healing Society (http://www.woundheal.org)European Tissue Repair Society (http://www.etrs.org)Wound Repair and Regeneration(http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1524-475X/issues) The official publication of theWound Healing Society and the European Tissue Repair Society.Journal of Burns and Wounds (http://www.ncbi.nlm.nih.gov/pmc/journals/211/)Fibrogenesis & Tissue Repair (http://www.fibrogenesis.com), an online open access journal about chronicwound healing and fibrogenesis.EWMA Journal (http://ewma.org/english/ewma-journal/latest-issues.html), Journal of the EuropeanWound Management AssociationGrace Bio-Labs, Wound Repair Article Links (http://www.gracebio.com/info-pages/wound-repair/wound-

repair-ref.html)Ostomy Wound Management (http://www.o-wm.com/) The official journal of the Association for theAdvancement of Wound Care.

Retrieved from "http://en.wikipedia.org/w/index.php?title=Wound_healing&oldid=646136962"

Categories: Skin physiology Traumatology Physiology Trauma surgery

This page was last modified on 8 February 2015, at 04:08.Text is available under the Creative Commons Attribution-ShareAlike License; additional terms mayapply. By using this site, you agree to the Terms of Use and Privacy Policy. Wikipedia is a registeredtrademark of the Wikimedia Foundation, Inc., a non-profit organization.