Wound healing 514458 225433566 2008-07-13T17:52:44Z Mike by 2895810 /* External links */ [[Image:Fluorescent wound healing.jpg|right|250px|thumb|A [[Fluorescence microscope|fluorescence micrograph]] of cells in ''[[Drosophila]]'' larvae healing after a puncture wound. The arrow points to cells that have fused to form [[syncytia]], and the arrowheads point to cells that are oriented to face the wound.<ref>{{cite journal|title=Cellular and genetic analysis of wound healing in ''Drosophila'' Larvae |journal= PLoS Biology|volume= 2|issue=8 |doi=10.1371/journal.pbio.0020239 |date=2004 | author=Galko MJ, Krasnow MA |url=http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020239| pages=e239}}</ref>]] '''Wound healing''', or '''wound repair''', is the body's natural process of regenerating [[dermis|dermal]] and [[Epidermis (skin)|epidermal]] [[Biological tissue|tissue]]. When an individual is [[wound]]ed, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage. These events overlap in time<ref name="Stadelmann">Stadelmann W.K., Digenis A.G. and Tobin G.R. (1998). Physiology and healing dynamics of chronic cutaneous wounds. ''The American Journal of Surgery'' '''176''' (2): 26S-38S. PMID 9777970.</ref> and may be artificially categorized into separate steps: the inflammatory, proliferative, and remodeling phases (Some authors consider healing to take place in four or more stages, by splitting different parts of inflammation or proliferation into separate steps.).<ref name="Quinn">Quinn, J.V. (1998). ''Tissue Adhesives in Wound Care''. Hamilton, Ont. B.C. Decker, Inc. Electronic book.</ref> In the inflammatory phase, [[bacterium|bacteria]] and debris are phagocytized 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]], [[collagen]] deposition, [[granulation tissue]] formation, epithelialization, and wound contraction.<ref name="Midwood">Midwood K.S., Williams L.V., and Schwarzbauer J.E. 2004. Tissue repair and the dynamics of the extracellular matrix. ''The International Journal of Biochemistry & Cell Biology'' '''36''' (6): 1031&ndash;1037. PMID 15094118.</ref> In angiogenesis, new [[blood vessel]]s grow from endothelial [[cell (biology)|cells]].<ref name="chang">Chang H.Y., Sneddon J.B., Alizadeh A.A., Sood R., West R.B., Montgomery K., Chi J.T., van de Rijn M, Botstein D., Brown P.O. (2004). [http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020007 Gene Expression Signature of Fibroblast Serum Response Predicts Human Cancer Progression: Similarities between Tumors and Wounds]. ''Public Library of Science'' '''2''' (2). PMID 14737219. Accessed [[January 20]], [[2008]]. </ref> In [[fibroplasia]] and granulation tissue formation, [[fibroblast]]s grow and form a new, provisional [[extracellular matrix]] (ECM) by excreting [[collagen]] and [[fibronectin]].<ref name="Midwood"/> In epithelialization, [[epithelial cell]]s crawl across the wound bed to cover it.<ref name="Garg">Garg, H.G. (2000). ''Scarless Wound Healing''. New York Marcel Dekker, Inc. Electronic book.</ref> In contraction, the wound is made smaller by the action of [[myofibroblast]]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]].<ref name="Midwood"/> In the maturation and remodeling phase, collagen is remodeled and realigned along tension lines and [[cell (biology)|cells]] that are no longer needed are removed by apoptosis. However, this process is not only complex but fragile, and susceptible to interruption or failure leading to the formation of chronic non-healing wounds. Factors which may contribute to this include diabetes, venous or arterial disease, old age, and infection. <ref name="Enoch">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''. Worldwidewounds.com.</ref> == Inflammatory phase == In the inflammatory phase (lag phase/resting phase), [[clotting cascade|clotting]] takes place in order to obtain [[hemostasis]], or stop blood loss, and various factors are released to attract [[cell (biology)|cells]] that [[phagocytosis|phagocytise]] debris, bacteria, and damaged tissue and release factors that initiate the proliferative phase of wound [[healing]]. ===Clotting cascade=== {{main|Coagulation}} [[Image:Drosophila wound syncytium.jpg|right|thumb|A [[syncytium]] forms in the [[epithelium]] of ''Drosophila'' when the fly is stabbed with a needle, forming a plug to staunch bleeding.<ref name="plosSync"> {{ cite journal|date=2004|title=The Molecular Biology of Wound Healing|Journal= PLoS Biology|volume= 2|issue=8|page= e278 |doi=10.1371/journal.pbio.0020278|url= http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.0020278 }} </ref>]] When [[tissue (biology)|tissue]] is first wounded, [[blood]] comes in contact with [[collagen]], triggering blood [[platelet]]s to begin secreting inflammatory factors.<ref name="Rosenberg and de la Torre, 2006">Rosenberg L., de la Torre J. (2006). [http://www.emedicine.com/plastic/topic457.htm Wound Healing, Growth Factors]. Emedicine.com. Accessed [[January 20]], [[2008]].</ref> Platelets also express [[glycoprotein]]s on their [[cell membrane]]s that allow them to stick to one another and to [[platelet aggregation|aggregate]], forming a mass.<ref name="Midwood"/> [[Fibrin]] and [[fibronectin]] cross-link together and form a plug that traps [[protein]]s and particles and prevents further blood loss.<ref name="Sandeman">Sandeman S.R., Allen M.C., Liu C., Faragher R.G.A., Lloyd A.W. (2000). Human keratocyte migration into collagen gels declines with in vitro ageing. ''Mechanisms of Ageing and Development'' '''119''' (3): 149-157. PMID 11080534. </ref> This fibrin-fibronectin plug is also the main structural support for the wound until collagen is deposited.<ref name="Midwood"/> Migratory cells use this plug as a matrix to crawl across, and platelets adhere to it and secrete factors.<ref name="Midwood"/> The clot is eventually lysed and replaced with [[granulation tissue]] and then later with collagen. ===Platelets=== 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]]s, including [[growth factor]]s.<ref name="Rosenberg and de la Torre, 2006"/> Growth factors stimulate cells to speed their rate of division. Platelets also release other proinflammatory factors like [[serotonin]], [[bradykinin]], [[prostaglandin]]s, [[prostacyclin]]s, [[thromboxane]], and [[histamine]]<ref name="Stadelmann"/>, which serve a number of purposes, including to increase cell proliferation and migration to the area and to cause [[blood vessel]]s to become dilated and porous. ===Vasoconstriction and vasodilation=== Immediately after a [[blood vessel]] is breached, ruptured [[cell membrane]]s release inflammatory factors like [[thromboxane]]s and [[prostaglandin]]s that cause the vessel to spasm to prevent blood loss and to collect inflammatory cells and factors in the area.<ref name="Stadelmann"/> This [[vasoconstriction]] lasts five to ten minutes and is followed by [[vasodilation]], a widening of blood vessels, which peaks at about 20 minutes post-wounding.<ref name="Stadelmann"/> Vasodilation is the result of factors released by platelets and other cells. The main factor involved in causing vasodilation is [[histamine]].<ref name="Stadelmann"/><ref name="Rosenberg and de la Torre, 2006"/> Histamine also causes blood vessels to become porous, allowing the tissue to become [[edema]]tous because proteins from the bloodstream leak into the extravascular space, which increases its [[osmolar load]] and draws water into the area.<ref name="Stadelmann"/> Increased [[porosity]] of blood vessels also facilitates the entry of inflammatory cells like [[leukocyte]]s into the wound site from the [[bloodstream]].<ref name="Dealey">Dealey C. (1999). ''The care of wounds: A guide for nurses''. Oxford ; Malden, Mass. Blackwell Science. Electronic book.</ref><ref name="Theoret">Theoret C.L. (2004). Update on wound repair. ''Clinical Techniques in Equine Practice'' '''3''' (2): 110-122.</ref> ===Polymorphonuclear neutrophils=== Within an hour of wounding, [[granulocyte|polymorphonuclear neutrophil]]s (PMNs) arrive at the wound site and become the predominant cells in the wound for the first three days after the injury occurs, with especially high numbers on the second day.<ref name="Scholar and Stadelmann">de la Torre J., Sholar A. (2006). [http://www.emedicine.com/plastic/topic477.htm Wound healing: Chronic wounds]. Emedicine.com. Accessed [[January 20]], [[2008]].</ref> They are attracted to the site by fibronectin, growth factors, and substances such as [[neuropeptide]]s and [[kinin]]s. Neutrophils phagocytise debris and bacteria and also kill bacteria by releasing [[free radical]]s in what is called a '[[respiratory burst]]'.<ref name="Greenhalgh">Greenhalgh D.G. (1998). The role of apoptosis in wound healing. ''The International Journal of Biochemistry & Cell Biology'' '''30''' (9): 1019&ndash;1030. PMID 9785465.</ref><ref name="muller">Muller M.J. , Hollyoak M.A., Moaveni Z., La T., Brown H., Herndon D.N., Heggers J.P. 2003. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin. ''Burns'' '''29''' (8): 834-836. PMID 14636760.</ref> They also cleanse the wound by secreting [[protease]]s that break down damaged tissue. Neutrophils usually undergo apoptosis once they have completed their tasks and are engulfed and degraded by [[macrophage]]s.<ref name="Martin">Martin P. and Leibovich. (2005). Inflammatory cells during wound repair: the good, the bad and the ugly. ''Trends in Cell Biology'' '''15''' (11): 599-607. PMID 16202600.</ref> Other leukocytes to enter the area include [[helper T cell]]s, which secrete [[cytokines]] to cause more T cells to divide and to increase inflammation and enhance vasodilation and vessel permeability.<ref name="Dealey"/><ref name="Santoro">Santoro M.M. and Gaudino G. (2005). Cellular and molecular facets of keratinocyte reepithelization during wound healing. ''Experimental Cell Research'' '''304''' (1): 274-286. PMID 15707592.</ref> T cells also increase the activity of macrophages.<ref name="Dealey"/> ===Macrophages=== Macrophages are essential to wound healing.<ref name="Scholar and Stadelmann"/> They replace PMNs as the predominant cells in the wound by two days after injury.<ref name="Expert Reviews">Expert Reviews in Molecular Medicine. (2003). [http://www-ermm.cbcu.cam.ac.uk/03005829a.pdf The phases of cutaneous wound healing]. '''5''': 1. Cambridge University Press. Accessed [[January 20]], [[2008]].</ref> Attracted to the wound site by growth factors released by platelets and other cells, [[monocyte]]s from the bloodstream enter the area through blood vessel walls.<ref name="Lorenz">Lorenz H.P. and Longaker M.T. (2003). [http://recon.stanford.edu/Articles/LorenzWH.pdf Wounds: Biology, Pathology, and Management]. Stanford University Medical Center. Accessed [[January 20]], [[2008]].</ref> Numbers of monocytes in the wound peak one to one and a half days after the injury occurs.<ref name="Santoro"/> Once they are in the wound site, monocytes mature into macrophages, the main cell type that clears the wound area of bacteria and debris.<ref name="Scholar and Stadelmann"/> The macrophage's main role is to phagocytise bacteria and damaged tissue, and it also debrides damaged tissue by releasing proteases.<ref name="Deodhar and Rana">Deodhar A.K., Rana R.E. (1997). [http://www.jpgmonline.com/article.asp?issn=0022-3859;year=1997;volume=43;issue=2;spage=52;epage=6;aulast=Deodhar Surgical physiology of wound healing: a review]. ''Journal of Postgraduate Medicine'' '''43''' (2): 52-56. PMID 10740722. Accessed [[January 20]], [[2008]].</ref> 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.<ref name="Rosenberg and de la Torre, 2006"/> Macrophages are stimulated by the low [[oxygen]] content of their surroundings to produce factors that induce and speed [[angiogenesis]].<ref name="Greenhalgh"/> and they also stimulate cells that reepithelialize the wound, create granulation tissue, and lay down a new [[extracellular matrix]].<ref name="merc">Mercandetti M., Cohen A.J. (2005). [http://www.emedicine.com/plastic/topic411.htm Wound Healing: Healing and Repair]. Emedicine.com. Accessed [[January 20]], [[2008]].</ref><Ref name=Stashak>Stashak T.S., Farstvedt E., Othic A. (2004). Update on wound dressings: Indications and best use. ''Clinical Techniques in Equine Practice'' '''3''' (2): 148-163.</ref> Because they secrete these factors, macrophages are vital for pushing the wound healing process into the next phase. Because inflammation plays roles in fighting infection and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to [[tissue (biology)|tissue]] damage if it lasts too long.<ref name="Midwood"/> 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]]. 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.<ref name="Scholar and Stadelmann"/> These changes indicate that the inflammatory phase is ending and the proliferative phase is underway.<ref name="Scholar and Stadelmann"/> == 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.<ref name="Falanga, 2005">Falanga V. (2005). Wound Healing. American Academy of Dermatology (AAD).</ref> 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.<ref name="Kuwahara">Kuwahara R.T. and Rasberry R. 2007. [http://www.emedicine.com/derm/topic533.htm Chemical Peels]. Emedicine.com. Accessed [[September 15]], [[2007]]. </ref> Because the activity of fibroblasts and epithelial cells requires oxygen, 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]]tous) due to the presence of [[capillary|capillaries]].<ref name="Kuwahara"/> In order to form new [[blood vessel]]s and provide oxygen and nutrients to the healing tissue.<ref name="romo">Romo T. and Pearson J.M. 2005. [http://www.emedicine.com/ent/topic13.htm Wound Healing, Skin]. Emedicine.com. Accessed [[December 27]], [[2006]].</ref> [[stem cell]]s called [[endothelial cell]]s originating from parts of uninjured blood vessels develop [[pseudopod]]ia and push through the [[ECM]] into the wound site. Through this activity, they establish new blood vessels.<ref name="Greenhalgh"/> To migrate, endothelial cells need [[collagenase]]s and [[plasminogen activator]] to degrade the clot and part of the ECM.<ref name="Stadelmann"/><ref name="Scholar and Stadelmann"/> [[Zinc]]-dependent [[metalloproteinase]]s digest [[basement membrane]] and ECM to allow cell proliferation and angiogenesis.<ref name="Lansdown">Lansdown A.B.G., Sampson B., and Rowe A. 2001. Experimental observations in the rat on the influence of cadmium on skin wound repair. ''International Journal of Experimental Pathology'', 82(1): 35-41. PMID 11422539.</ref> [[Endothelial cell]]s are also attracted to the wound area by fibronectin found on the fibrin scab and by growth factors released by other cells.<ref name="romo"/> Endothelial growth and proliferation is also stimulated by [[Hypoxia (medical)|hypoxia]] and presence of [[lactic acid]] in the wound.<ref name="Falanga, 2005"/> In a low-oxygen environment, macrophages and platelets produce angiogenic factors which attract endothelial cells [[chemotaxis|chemotactically]]. When macrophages and other growth factor-producing cells are no longer in a hypoxic, lactic acid-filled environment, they stop producing angiogenic factors.<ref name="Greenhalgh"/> Thus, when tissue is adequately [[perfusion|perfused]], migration and proliferation of endothelial cells is reduced. Eventually blood vessels that are no longer needed die by [[apoptosis]].<ref name="romo"/> ===Fibroplasia and granulation tissue formation=== Simultaneously with angiogenesis, [[fibroblast]]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.<ref name="Scholar and Stadelmann"/> By the end of the first week, fibroblasts are the main cells in the wound<ref name="Stadelmann"/> Fibroplasia ends two to four weeks after wounding. In the first two or three days after injury, fibroblasts mainly proliferate and migrate, while later, they are the main cells that lay down the collagen matrix in the wound site.<ref name="Stadelmann"/> Fibroblasts from normal tissue migrate into the wound area from its margins. Initially fibroblasts use the fibrin scab formed in the inflammatory phase to migrate across, adhering to fibronectin.<ref name="romo"/> Fibroblasts then deposit [[ground substance]] into the wound bed, and later collagen, which they can adhere to for migration.<ref name="Rosenberg and de la Torre, 2006"/> [[Granulation tissue]] is needed to fill the void that has been left by a large, open wound that crosses the basement membrane. It begins to appear in the wound even 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 ECM. The provisional ECM is different in composition from the ECM in normal tissue and includes fibronectin, collagen, [[glycosaminoglycan]]s, and [[proteoglycan]]s.<ref name="romo"/> Its main components are fibronectin and [[hyaluronan]], which create a very hydrated matrix and facilitate cell migration.<ref name="Lorenz"/> Later this provisional matrix is replaced with an ECM that more closely resembles that found in non-injured tissue. Fibroblasts deposit ECM molecules like [[glycoprotein]]s, [[glycosaminoglycan]]s (GAGs), [[proteoglycan]]s, [[elastin]], and [[fibronectin]], which they can then use to migrate across the wound (Cohen, 2005). 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 [[scar|scarring.]] ====Collagen deposition==== One of fibroblasts' most important duties is the production of [[collagen]].<ref name="Kuwahara"/> Fibroblasts begin secreting appreciable collagen by the second or third post-wounding day,<ref name="romo"/> and its deposition peaks at one to three weeks.<ref name="merc"/> Collagen production continues rapidly for two to four weeks, after which its destruction matches its production and so its growth levels off.<ref name="Greenhalgh"/> 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]].<ref name="Greenhalgh"/> Also, cells involved in inflammation, angiogenesis, and connective tissue construction attach to, grow and differentiate on the collagen matrix laid down by fibroblasts.<ref name="Ruszczak">Ruszczak Z. 2003. Effect of collagen matrices on dermal wound healing. ''Advanced Drug Delivery Reviews'', 55(12): 1595&ndash;1611. PMID 14623403</ref> 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 maturation phase. Granulation gradually ceases and fibroblasts decrease in number in the wound once their work is done.<ref name="DiPietro">DiPietro L.A. and Burns A.L., Eds. 2003. Wound Healing: Methods and Protocols. ''Methods in Molecular Medicine''. Totowa, N.J. Humana Press. Electronic book.</ref> 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.<ref name="Stadelmann"/> ===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.<ref name="romo"/> [[Stratum basale|Basal]] [[keratinocyte]]s from the wound edges and [[dermal appendage]]s such as [[hair follicle]]s, [[sweat glands]] and [[sebacious gland|sebacious (oil) glands]] are the main cells responsible for the epithelialization phase of wound healing.<ref name="DiPietro"/> 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.<ref name="Bartkova">Bartkova J., Grøn B., Dabelsteen E., and Bartek J. 2003. Cell-cycle regulatory proteins in human wound healing. ''Archives of Oral Biology'', 48(2): 125-132. PMID 12642231.</ref>. 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.<ref name="Mulvaney">Mulvaney M. and Harrington A. 1994. [http://web.archive.org/web/20031218072356/http://www.vnh.org/MilitaryDerm/Ch7.pdf Chapter 7: Cutaneous trauma and its treatment]. In, ''Textbook of Military Medicine: Military Dermatology''. Office of the Surgeon General, Department of the Army. Virtual Naval Hospital Project. Accessed through web archive on [[September 15]], [[2007]].</ref> Thus the time of onset of migration is variable and may occur about one day after wounding.<ref name="larjava">Larjava H., Koivisto L., and Hakkinen L. 2002. Chapter 3: Keratinocyte Interactions with Fibronectin During Wound Healing. In, Heino, J. and Kahari, V.M. ''Cell Invasion''. Medical Intelligence Unit ; 33. Georgetown, Tex., Austin, Tex Landes Bioscience, Inc. Electronic book.</ref> Cells on the wound margins proliferate on the second and third day post-wounding in order to provide more cells for migration.<ref name="merc"/> 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.<ref name="romo"/> However, if the [[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]] that are lined with viable keratinocytes.<ref name="merc"/> If the wound is very deep, skin appendages may also be ruined and migration can only occur from wound edges.<ref name="Mulvaney"/> Migration of keratinocytes over the wound site is stimulated by lack of [[contact inhibition]] and by chemicals such as [[nitric oxide]].<ref name="Witte and Barbul">Witte M.B. and Barbul A. 2002. Role of nitric oxide in wound repair. ''The American Journal of Surgery'', 183(4): 406-412. PMID 11975928.</ref> 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 the ECM.<ref name="Santoro"/> [[Transmembrane]] [[receptor (biochemistry)|receptor]] [[protein]]s called [[integrin]]s, which are made of [[glycoprotein]]s and normally anchor the cell to the basement membrane by its [[cytoskeleton]], are released from the cell's intermediate filaments and relocate to [[actin]] filaments to serve as attachments to the ECM for [[pseudopod]]ia during migration.<ref name="Santoro"/> Thus keratinocytes detach from the basement membrane and are able to enter the wound bed.<ref name="Falanga, 2005"/> Before they begin migrating, keratinocytes change shape, becoming longer and flatter and extending cellular processes like [[pseudopod|lamellipodia]] and wide processes that look like ruffles.<ref name="Lorenz"/> [[Actin]] filaments and [[pseudopod]]ia form.<ref name="Falanga, 2005"/> During migration, [[integrin]]s on the pseudopod attach to the ECM, and the actin filaments in the projection pull the cell along.<ref name="Santoro"/> The interaction with molecules in the ECM through integrins further promotes the formation of actin filaments, lamellipodia, and [[pseudopod|filopodia]].<ref name="Santoro"/> Epithelial cells climb over one another in order to migrate.<ref name="DiPietro"/> This growing sheet of epithelial cells is often called the epithelial tongue.<ref name="Bartkova"/> 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 as well.<ref name="Bartkova"/> The more quickly this migration occurs, the less of a scar there will be.<ref name="Son">Son H.J. Bae H.C., Kim H.J., Lee D.H., Han D.W., and Park J.C. 2005. Effects of β-glucan on proliferation and migration of fibroblasts. ''Current Applied Physics'', 5(5): 468-471. </ref> [[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 an attachment site to crawl across.<ref name="Lorenz"/><ref name="Deodhar and Rana"/><ref name="DiPietro"/> As keratinocytes migrate, they move over granulation tissue but underneath the [[scab]] (if one was formed), separating it from the underlying tissue.<ref name="DiPietro"/><ref name="larjava"/> 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.<ref name="Deodhar and Rana"/><ref name="romo"/><ref name="DiPietro"/><ref name="Falanga, 2004">Falanga V. 2004. The chronic wound: impaired healing and solutions in the context of wound bed preparation. ''Blood Cells, Molecules, and Diseases'', 32(1): 88-94. PMID 14757419.</ref> To make their way along the tissue, keratinocytes must dissolve the clot, debris, and parts of the ECM in order to get through.<ref name="larjava"/><ref name="Etscheid">Etscheid M., Beer N., and Dodt J. 2005. The hyaluronan-binding protease upregulates ERK1/2 and PI3K/Akt signalling pathways in fibroblasts and stimulates cell proliferation and migration. ''Cellular Signalling'', 17(12): 1486&ndash;1494. PMID 16153533.</ref> They secrete [[plasminogen activator]], which activates [[plasmin]] to dissolve the scab. Cells can only migrate over living tissue,<ref name="DiPietro"/> 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.<ref name="larjava"/> Keratinocytes also dissolve the basement membrane, using instead the new ECM laid down by fibroblasts to crawl across.<ref name="Santoro"/> 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.<ref name="Deodhar and Rana"/> Proliferation behind migrating keratinocytes normally begins a few days after wounding<ref name="Mulvaney"/> and occurs at a rate that is 17 times higher in this stage of epithelialization than in normal tissues.<ref name="Deodhar and Rana"/> Until the entire wound area is resurfaced, the only epithelial cells to proliferate are at the wound edges.<ref name="Bartkova"/> 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.<ref name="Bayram">Bayram Y., Deveci M., Imirzalioglu N., Soysal Y., and Sengezer M. 2005. The cell based dressing with living allogenic keratinocytes in the treatment of foot ulcers: a case study. ''British Journal of Plastic Surgery'', 58(7): 988-996. PMID 16040019. Accessed [[September 15]], [[2007]].</ref> Keratinocytes continue migrating across the wound bed until cells from either side meet in the middle, at which point [[contact inhibition]] causes them to stop migrating.<ref name="Lorenz"/> When they have finished migrating, the keratinocytes secrete the proteins that form the new basement membrane.<ref name="Lorenz"/> Cells reverse the morphological changes they underwent in order to begin migrating; they reestablish [[desmosome]]s and [[hemidesmosome]]s and become anchored once again to the basement membrane.<ref name="Santoro"/> [[Stratum basale|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.<ref name="Lorenz"/> ===Contraction===<!-- This section is linked from [[Contraction]] --> Around a week after the wounding takes place, fibroblasts have differentiated into [[myofibroblast]]s and the wound begins to contract<ref name="Eichler and Carlson">Eichler M.J. and Carlson M.A. 2005. Modeling dermal granulation tissue with the linear fibroblast-populated collagen matrix: A comparison with the round matrix model. ''Journal of Dermatological Science'', 41(2): 97-108. PMID 16226016. Accessed [[September 15]], [[2007]].</ref> In [[full thickness]] wounds, contraction peaks at 5 to 15 days post wounding.<ref name="romo"/> Contraction can last for several weeks<ref name="Mulvaney"/> and continues even after the wound is completely reepithelialized.<ref name="Stadelmann"/> If contraction continues for too long, it can lead to disfigurement and loss of function.<ref name="Hinz">Hinz B. 2005. Masters and servants of the force: The role of matrix adhesions in myofibroblast force perception and transmission. ''European Journal of Cell Biology'' 85(3-4): 175-181. PMID 16546559. Accessed [[September 15]], [[2007]].</ref> Contraction occurs in order to reduce the size of the wound. A large wound can become 40 to 80% smaller after contraction.<ref name="Lorenz"/><ref name="DiPietro"/>. 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.<ref name="romo"/> 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.<ref name="Eichler and Carlson"/> At first, contraction occurs without myofibroblast involvement.<ref name="Mirastschijski">Mirastschijski U., Haaksma C.J., Tomasek J.J., and Ågren M.S. 2004. Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. ''Experimental Cell Research'', 299(2): 465-475. PMID 15350544.</ref> Later, fibroblasts, stimulated by growth factors, differentiate into myofibroblasts. Myofibroblasts, which are similar to smooth muscle cells, are responsible for contraction.<ref name="Mirastschijski"/> Myofibroblasts contain the same kind of actin as that found in [[smooth muscle]] cells.<ref name="Hinz"/> 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.<ref name="Deodhar and Rana"/> 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.<ref name="Mirastschijski"/> Myofibroblasts have many such adhesions, which allow them to pull the ECM when they contract, reducing the wound size.<ref name="Hinz"/> In this part of contraction, closure occurs more quickly than in the first, myofibroblast-independent part.<ref name="Mirastschijski"/> As the actin in myofibroblasts contracts, the wound edges are pulled together. Fibroblasts lay down collagen to reinforce the wound as myofibroblasts contract<ref name="Stadelmann"/> The contraction stage in proliferation ends as myofibroblasts stop contracting and commit apoptosis.<ref name="Hinz"/> 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.<ref name="Scholar and Stadelmann"/> These events signal the onset of the maturation stage of wound healing. == Maturation and remodeling phase== When the levels of collagen production and degradation equalize, the maturation phase of tissue repair is said to have begun.<ref name="Greenhalgh"/> The maturation phase can last for a year or longer, depending on the size of the wound and whether it was initially closed or left open.<ref name="merc"/> 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.<ref name="Dealey"/> Originally disorganized collagen fibers are rearranged, cross-linked, and aligned along tension lines.<ref name="Lorenz"/> As the phase progresses, the [[tensile strength]] of the wound increases, with the strength approaching 50% that of [[tissue (biology)|normal tissue]] by three months after injury and ultimately becoming as much as 80% as strong as normal tissue.<ref name="merc"/> Since activity at the wound site is reduced, the scar loses its erythematous appearance as [[blood vessel]]s that are no longer needed are removed by [[apoptosis]].<ref name="Greenhalgh"/> 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]] <ref name="Midwood"/> such as a [[venous ulcer]] or pathological scarring such as a [[keloid scar]].<ref name="O'Leary">O'Leary, R., Wood, E.J., and Guillou P.J. 2002. Pathological scarring: strategic interventions. ''European Journal of Surgery'', 168(10):523-534. PMID 12666691.</ref><ref name="Desmouliere">Desmouliere, A., Chaponnier, C., and Gabbiani, G. 2005. Tissue repair, contraction, and the myofibroblast. ''Wound Repair and Regeneration'', 3(1):7-12. PMID 15659031.</ref> ==Estrogen, Testosterone, and DHEA affect wound healing== In humans and mice, [[estrogen]] and [[DHEA]] promote wound healing and [[testosterone]] inhibits healing except as to severe burns.<ref>http://www.woundsresearch.com Feature: Sex Hormones and Wound Healing - Desiree May Oh, MD, and Tania J. Phillips, MD</ref> ==References== {{reflist|2}} ==External links== *Bauer S.M., Bauer R.J., Liu Z.J., Chen H., Goldstein L., and Velázquez O.C. 2005. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15874936&query_hl=3 Vascular endothelial growth factor-C promotes vasculogenesis, angiogenesis, and collagen constriction in three-dimensional collagen gels]. Journal of Vascular Surgery, 41(4): 699-707. Accessed [[December 31]], [[2006]]. * [http://www.bterfoundation.org/ BioTherapeutics Education and Research Foundation] *Brain S.D. 1997. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9403332&query_hl=7 Sensory neuropeptides: their role in inflammation and wound healing]. Immunopharmacology, 37 (2-3): 133-152. Accessed [[December 31]], [[2006]]. *Ingber D. [http://www.childrenshospital.org/cfapps/research/data_admin/Site97/mainpageS97P5.html How wounds heal and tumors form] Children's Hospital Boston research department. *[http://www.waterpharmacyonline.com Healing water] web site at the Moscow State University, providing information about alternative medicine water treatment *[http://www.ucihs.uci.edu/com/pathology/sherman/home_pg.htm Maggot Therapy Project] web site at the University of California, Irvine, list of maggot therapy practitioners *[http://www.monarchlabs.com/ suppliers of Medical Maggots] (disinfected Phaenicia sericata larvae), picture of Medical Maggots vial *Mustoe T. 2005. [http://www.pasteur.fr/applications/euroconf/tissuerepair/Mustoe_abstract.pdf 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&ndash;18, 2005. Accessed [[December 31]], [[2006]]. *Revis D.R. and Seagel M.B. 2006. [http://www.emedicine.com/plastic/topic392.htm Skin, Grafts]. Emedicine.com. Accessed [[December 31]], [[2006]]. *Stillman R.M. 2006. [http://www.emedicine.com/med/topic2754.htm Wound Care]. Emedicine.com. Accessed [[December 31]], [[2006]]. *Wilhelmi B.J. 2006. [http://www.emedicine.com/plastic/topic537.htm Wound Healing, widened and hypertrophic scars]. Emedicine.com. Accessed [[December 31]], [[2006]]. *Journal of Burns and Wounds [http://www.journalofburnsandwounds.com] {{pathology}} [[Category:Dermatology]] [[Category:traumatology]] [[Category:physiology]] [[ar:التئام (طبّ)]] [[de:Wundheilung]] [[es:Cicatrización]] [[sk:Hojenie rán]] [[zh:傷口癒合]]