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METU-Gene
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| - | <... | + | <[[Image:Hand Abrasion - 32 minutes after injury.JPG|thumb|Hand abrasion, 30 minutes after injury.]] |
| + | [[Image:Hand Abrasion - 2 days 22 hours 12 minutes after injury.JPG|thumb|2 days after injury.]] | ||
| + | [[Image:Hand Abrasion - 17 days 11 hours 30 minutes after injury.JPG|thumb|17 days after injury.]] | ||
| + | [[Image:Hand Abrasion - 30 days 4 hours 43 minutes after injury.JPG|thumb|30 days after injury.]] | ||
| + | Wound healing, or wound repair, is an intricate process in which the skin (or some other organ) repairs itself after injury.<ref "Nguyen">Nguyen, D.T., Orgill D.P., Murphy G.F. (2009). Chapter 4: The pathophysiologic basis for wound healing and cutaneous regeneration. ''Biomaterials For Treating Skin Loss''. CRC Press (US) & Woodhead Publishing (UK), Boca Raton/Cambridge, p. 25-57. (ISBN 978-1-4200-9989-9, ISBN 978-1-84569-363-3)</ref> In normal skin, the epidermis (outermost layer) and dermis (inner or deeper layer) exists in a steady-state equilibrium, forming a protective barrier against the external environment. Once the protective barrier is broken, the normal (physiologic) process of wound healing is immediately set in motion. The classic model of wound healing is divided into three or four sequential, yet overlapping, phases: (1) hemostasis (not considered a phase by some authors), (2) inflammatory, (3) proliferative and (4) remodeling. | ||
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| + | Upon injury to the skin, a set of complex biochemical events takes place in a closely orchestrated cascade to repair the damage.<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 Hamilton, Ont. B.C. Decker, Inc. Electronic book</ref> Within minutes post-injury, platelets (thrombocytes) aggregate at the injury site to form a fibrin clot. This clot acts to control active bleeding ([[hemostasis]]). | ||
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| + | In the inflammatory phase, [[bacteria]] and debris are phagocytized and removed, and factors are released that cause the migration and division of cells involved in the proliferative phase. | ||
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| + | 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): 1031–1037. PMID 15094118.</ref> In angiogenesis, new blood vessels are formed by vascular endothelial 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"/> Concurrently, re-epithelialization of the epidermis occurs, in which [[epithelial cell]]s proliferate and 'crawl' atop the wound bed, providing cover for the new tissue.<ref name="Garg">Garg, H.G. (2000). ''Scarless Wound Healing''. New York Marcel Dekker, Inc. Electronic book.</ref> | ||
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| + | 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"/> | ||
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| + | 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. | ||
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| + | 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]]. | ||
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| + | ===Clotting cascade=== | ||
| + | {{main|Coagulation}} | ||
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| + | 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"/> | ||
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| + | [[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. | ||
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| + | ===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> | ||
| + | === Decline of inflammatory phase=== | ||
| + | As inflammation dies down, fewer inflammatory factors are secreted, existing ones are broken down, and numbers of neutrophils and macrophages are reduced at the wound site.<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"/> | ||
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| + | Because inflammation plays roles in fighting infection, clearing debris and inducing the proliferation phase, it is a necessary part of healing. However, inflammation can lead to [[tissue (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]]. | ||
| + | |||
| + | == 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. ''The proliferative phase is also called the reconstruction phase.'' | ||
| + | ===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 and nutrients, angiogenesis is imperative for other stages in wound healing, like epidermal and fibroblast migration. The tissue in which angiogenesis has occurred typically looks red (is [[erythema]]tous) due to the presence of [[capillary|capillaries]].<ref name="Kuwahara"/> | ||
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| + | [[Stem cell]]s of [[endothelial cell]]s, originating from parts of uninjured blood vessels, develop [[pseudopod]]ia and push through the [[Extracellular matrix|ECM]] into the wound site to establish new blood vessels.<ref name="Greenhalgh"/> | ||
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| + | [[Endothelial cell]]s are attracted to the wound area by fibronectin found on the fibrin scab and [[chemotaxis|chemotactically]] by angiogenic factors released by other cells,<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> e.g. from macrophages and platelets when in a low-oxygen environment. Endothelial growth and proliferation is also directly stimulated by [[Hypoxia (medical)|hypoxia]], and presence of [[lactic acid]] in the wound.<ref name="Falanga, 2005"/> | ||
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| + | 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 migration, 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> | ||
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| + | 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"/> | ||
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| + | ====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"/> | ||
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| + | 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): 1595–1611. PMID 14623403</ref> | ||
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| + | 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"/> | ||
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| + | ===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. | ||
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| + | 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"/> | ||
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| + | 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"/> | ||
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| + | 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"/> | ||
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| + | 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"/> | ||
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| + | 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> | ||
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| + | [[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"/> | ||
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| + | 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): 1486–1494. PMID 16153533.</ref> They secrete [[plasminogen activator]], which activates [[plasminogen]], turning it into [[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"/> | ||
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| + | 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"/> | ||
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| + | 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> Growth factors are also important for the innate immune defense of skin wounds by stimulation of the production of antimicrobial peptides in keratinocytes.<ref name="Sorensen">Sorensen OE, Thapa DR, Roupé KM, "et al.". (2006). Injury-induced innate immune response in human skin mediated by transactivation of the epidermal growth factor receptor. ''The Journal of Clinical Investigation'', 116(7): 1878-85. PMID 16778986. Accessed [[June 15]], [[2006]].</ref> | ||
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| + | 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"/> | ||
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| + | ===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> | ||
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| + | 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"/> | ||
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| + | 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"/> | ||
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| + | 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"/> | ||
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| + | 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 red appearance as [[blood vessel]]s that are no longer needed are removed by [[apoptosis]].<ref name="Greenhalgh"/> | ||
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| + | 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> | ||
| + | |||
| + | ==Primary, Secondary, and Tertiary Intention== | ||
| + | '''Primary Intention:''' | ||
| + | *When wound edges are directly next to one another | ||
| + | *Little tissue loss | ||
| + | *Minimal scarring occurs | ||
| + | *Most surgical wounds heal by first intention healing | ||
| + | *Wound closure is performed with sutures, staples, or adhesive at the time of initial evaluation | ||
| + | *examples:well repaired lacerations,well reduced bone fractures,healing after flap surgery. | ||
| + | |||
| + | '''Secondary Intention:''' | ||
| + | *The wound is allowed to granulate | ||
| + | *Surgeon may pack the wound with a gauze or use a drainage system | ||
| + | *Granulation results in a broader scar | ||
| + | *Healing process can be slow due to presence of drainage from infection | ||
| + | *Wound care must be performed daily to encourage wound debris removal to allow for granulation tissue formation | ||
| + | *examples:gingivectomy,gingivoplasty,tooth extraction sockets, poorly reduced fractures. | ||
| + | |||
| + | '''Tertiary Intention''' (Delayed primary closure): | ||
| + | *The wound is initially cleaned, debrided and observed, typically 4 or 5 days before closure. | ||
| + | *The wound is purposely left open | ||
| + | *examples:healing of wounds by use of tissue grafts. | ||
| + | |||
| + | ==Overview of involved growth factors== | ||
| + | Following are the main [[growth factors]] involved in wound healing: | ||
| + | |||
| + | {|class="wikitable" | ||
| + | ! Growth factor !! Abbreviation !! Main origins !! Effects | ||
| + | |- | ||
| + | ! [[Epidermal growth factor]] | ||
| + | | EGF | ||
| + | | | ||
| + | *Activated [[macrophages]] | ||
| + | *[[Salivary glands]] | ||
| + | *[[Keratinocytes]] | ||
| + | | | ||
| + | *Keratinocyte and fibroblast [[mitogen]] | ||
| + | *Keratinocyte migration | ||
| + | *[[Granulation tissue]] formation | ||
| + | |- | ||
| + | ! [[Keratinocyte growth factor]] | ||
| + | | KGF | ||
| + | | | ||
| + | *Fibroblasts | ||
| + | | | ||
| + | *Keratinocyte migration, proliferation and differentiation | ||
| + | |- | ||
| + | |colspan=4| <font size=1> Unless else specified in boxes, then reference is: <ref name=Kumar3-1> Table 3-1 in: {{cite book |author=Mitchell, Richard Sheppard; Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson |title=Robbins Basic Pathology|publisher=Saunders |location=Philadelphia |year= 2007|pages= |isbn=1-4160-2973-7 |oclc= |doi=}} 8th edition. </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]]. | ||
| + | *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.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 | ||
| + | *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 17–18, 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] | ||
| + | *[http://www.fibrogenesis.com Fibrogenesis & Tissue Repair], an online open access journal about chronic wound healing and fibrogenesis. | ||
| + | |||
| + | {{pathology}} | ||
| + | {{Wound healing}} | ||
| + | |||
| + | [[Category:Skin physiology]] | ||
| + | [[Category:Traumatology]] | ||
| + | [[Category:Physiology]] | ||
| + | |||
| + | [[ar:التئام (طب)]] | ||
| + | [[de:Wundheilung]] | ||
| + | [[es:Cicatrización]] | ||
| + | [[fr:Cicatrisation]] | ||
| + | [[it:Guarigione delle ferite]] | ||
| + | [[sk:Hojenie rán]] | ||
| + | [[zh:傷口癒合]] | ||
| + | html> | ||
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