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Home Books Fitzpatrick's Dermatology in General Medicine, 8e. Previous Chapter. Next Chapter. Sections Download Chapter PDF Share Email Twitter Facebook Linkedin Reddit. AMA Citation Falanga V, Iwamoto S. Chapter Mechanisms of Wound Repair, Wound Healing, and Wound Dressing.

In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Goldsmith L. Lowell A. Goldsmith, et al. Fitzpatrick's Dermatology in General Medicine, 8e.

The McGraw-Hill Companies; Accessed February 14, APA Citation Falanga V, Iwamoto S. mechanisms of wound repair, wound healing, and wound dressing. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. The McGraw-Hill Companies. MLA Citation Falanga V, Iwamoto S.

Download citation file: RIS Zotero. Reference Manager. Autosuggest Results. Jump to a Section Mechanisms of Wound Repair, Wound Healing, and Wound Dressing: Introduction Introduction Phases of Wound Healing Extracellular Matrix ECM Moist Wound Healing and the Repair Process Wound Healing of Skin Grafts Chronic Wounds and Impaired Healing Other Therapies for Impaired Healing Conclusions References.

Sections View Full Chapter Figures Tables Videos Annotate. Print Wound Repair at a Glance Acute and chronic wounds are different but overlap.

In acute wounds, there is an orderly progression from injury to coagulation, inflammation, proliferation, cell migration, and tissue modeling. In the initial phases, a wide range of growth factors, including platelet-derived growth factor and transforming growth factor-β1, play an important role.

MMP-1, MMP-9, and MMP are essential for remodeling. Moist wounds heal faster, and a variety of wound dressings are now available to fit this requirement.

They include transparent films, hydrocolloids, foams, alginates, gels, and collagen-based products. Chronic wounds are different from acute wounds in that the one-way relationship between the different phases is lost.

Chronic wounds are the complex result of ischemia, pressure, and infection; healing is highly dependent on these factors. Wound healing of skin grafts is also different, as it is completely dependent on revascularization, be it true neovascularization or inosculation. Get Free Access Through Your Institution Learn how to see if your library subscribes to McGraw Hill Medical products.

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Sign in via Shibboleth. You already have access! Classical endocrine hormones are molecules that are synthesized by specialized tissue and secreted into the blood stream which are then carried to distant target tissue where they interact with specific cellular receptor proteins and influence the expression of genes that ultimately regulate the physiological actions of the target cell.

It has been known for decades that alterations in endocrine hormones can alter wound healing. Diabetic patients frequently develop chronic wounds due to multiple direct and indirect effects of the inadequate insulin action on wound healing.

Patients receiving anti-inflammatory glucocorticoids for extended periods are also at risk of developing impaired wound healing due to the direct suppression of collagen synthesis in fibroblasts and the extended suppression of inflammatory cell function.

The association of oestrogen with healing was recently reported by Ashcroft and colleagues 37 when they observed that healing of skin biopsy sites in healthy, postmenopausal women was significantly slower than in healthy premenopausal women.

Molecular analyses of the wound sites indicated that TGF-β protein and mRNA levels were dramatically reduced in postmenopausal women in comparison to sites from premenopausal women.

However, the rate of healing of wounds in postmenopausal women taking oestrogen replacement therapy occurred as rapidly as in premenopausal women.

Furthermore, molecular analyses of wounds in postmenopausal women treated with oestrogen replacement therapy demonstrated elevated levels of TGF-β protein and mRNA that were similar to levels in wounds from premenopausal women.

Aging was also associated with elevated levels of MMPs and decreased levels of TIMPs in skin wounds, which were reversed by oestrogen treatment. Conditions that promote chronic wounds are repeated trauma, foreign bodies, pressure necrosis, infection, ischemia, and tissue hypoxia.

These wounds share a chronic inflammatory state characterized by an increased number of neutrophils, macro-phages, and lymphocytes which produce inflammatory cytokines, such as TNF-α, IL-1 and IL In vitro studies have shown that TNF- α and IL-1 increase expression of MMPs and down-regulate expression of TIMP in a variety of cells including macrophages, fibroblasts, keratinocytes, and endothelial cells.

All MMPs are synthesized as inactive proenzymes, and they are activated by proteolytic cleavage of the pro-MMP. Serine proteases, such as plasmin, as well as the membrane type MMPs can activate MMPs. Another serine protease, neutrophil elastase, is also present in increased concentrations in chronic wounds, and is very important in directly destroying extracellular matrix components and in destroying the TIMPs, which indirectly increases the destructive activity of MMPs.

Nwomeh and colleagues 23 further describe this common pathway in chronic wounds as a self-perpetuating environment in which chronic inflammation produces elevated levels of reactive oxygen species and degradative enzymes that eventually exceed their beneficial actions of destroying bacterial and debriding the wound bed and produce destructive effects that help to establish a chronic wound.

Based on these biochemical analyses of the molecular environments of acute and chronic human wounds, it is possible to propose a general model of differences between healing and chronic wounds.

As shown in Figure In contrast, the molecular environments of chronic wounds generally have the opposite characteristics, i. Comparison of the Molecular and Cellular Environments of Healing and Chronic Wounds. Elevated levels of cytokines and proteases in chronic wounds reduce mitogenic activities and response of wound cells, impairing healing.

Mechanisms involved in the creation and perpetuation of chronic wounds are varied and depend on the individual wounds. In general, the inability of chronic venous stasis ulcers to heal appears to be related to impairment in wound epithelialization. The wound edges show hyperproliferative epidermis under microscopy, even though further immunohistochemical studies revealed optimal conditions for keratinocyte recruitment, proliferation, and differentiation.

The extracellular matrix and the expression of integrin receptors by keratinocytes that allow them to translocate play an important regulatory role in epithelialization. After receiving the signal to migrate, epidermal cells begin by disassembling their attachments from basement membrane and neighboring cells.

They then travel over a provisional matrix containing fibrinogen, fibronectin, vitronectin, and tenascin and stop when they encounter laminin. During this process, keratinocytes are producing fibronectin, and continue to do so until the epithelial cells contact, at which time they again begin manufacturing laminin to regenerate the basement membrane.

There is evidence that the interaction between the integrin receptors on keratinocytes with the ECM will transform resting cells to a migratory phenotype. Integral in this transformation is the alteration in the pattern of integrin receptors expressed.

After epithelialization is completed, integrin expression reverts back to the resting pattern. To further complicate this process, growth factors are involved in mediating keratinocyte activation, integrin expression, and in alterations in the matrix.

Growth factors are able to differentially affect these processes. For example, TGF-β is able to promote epithelial migration while inhibiting proliferation. Although TGF-β induces the necessary integrin expression for migration, the cells behind those at the leading edge have little proliferative ability and so epithelial coverage of the wound is inhibited.

Some chronic wounds may be deficient in TGF-β and its receptor. Chronic wounds have also been demonstrated to have elevated matrix degrading enzymes and decreased levels of inhibitors for these enzymes. Pressure ulcers, unlike chronic venous stasis ulcers, appear to have difficulty in healing related to impairment of ECM production.

Studies have indicated that neutrophil elastase present in chronic wounds can degrade peptide growth factors and is responsible for degrading fibronectin.

Pressure ulcers have also shown an increase in matrix metalloproteinases and in plasminogen activators in tissue. Chronic wound fluids demonstrate increased levels of gelatinases MMP-2 and MMP Levels of MMP-1 and MMP-8 were also found to be higher in pressure ulcers and in venous stasis ulcers than in acute healing wounds.

In addition, several of the endogenous proteinase inhibitors were shown to be decreased in chronic wounds. Proteinase inhibitors serve a regulatory role in matrix degradation by containing the matrix-degrading enzymes. Factors that promote MMP production or activation could counteract the effectiveness of proteinase inhibitors, for example the destruction of TIMP by neutrophil elastase.

The tissue inhibitor level to MMP ratio may indicate an imbalance which contributes to the wound chronicity. Although the aetiologies and the physical characteristics for the various types of chronic wounds are different, there is a common trend in their biochemical profiles. The precise pattern of growth factor expression in the different types of chronic wounds is not yet known; but it has been determined that there is generally a decreased level of growth factors and their receptors in chronic wound fluids.

The absolute levels of growth factors may not be as important as the relative concentrations necessary to replace the specific deficiencies in the tissue repair processes. For the treatment of chronic wounds, Robson 43 proposed that growth factor therapy be tailored to the deficiency in the repair process.

Therefore, the effectiveness of the therapy is predicated on adequate growth factor levels and the expression of their receptors balanced against receptor degradation by proteases and the binding of growth factors by macromolecules such as macroglobulin and albumin.

Studies that evaluated topical growth factor treatment of chronic wounds, such as PDGF in diabetic foot ulcers and EGF in chronic venous stasis ulcers, have shown an improvement in healing. These findings have led to the hypothesis that altering the cytokine profile of chronic wounds through the use of MMP inhibitors, addition of growth factors, and the elimination of inflammatory tissue and proteases by debridement would shift the wound microenvironment towards that of an acute wound, thereby improve healing.

Current treatment strategies are being developed to address the deficiencies growth factor and protease inhibitor levels and excesses MMPs, neutrophil elastase, and serine protease levels in the chronic wound microenvironment. Although the more specific and sophisticated treatments remain in the lab at this time such as the new potent, synthetic inhibitors of MMPs and the naturally occurring protease inhibitors, TIMP-1 and 1-antitrypsin, available by recombinant DNA technology, the use of gene therapy in the treatment of chronic diabetic foot ulcers is currently being evaluated in a clinical trial.

A phase III clinical trial is underway to determine the efficacy of keratinocyte growth factor-2 KGF-2 in the treatment of chronic venous stasis ulcers. The treatment strategy to add growth factor to a chronic wound has been in place for the past several years. Other approaches to the treatment of chronic wounds have been to remove the increased protease levels.

This is in part the strategy of a vacuum-assisted negative pressure wound dressing 47 and in the recent development of dressings that bind and remove MMPs from the wound fluid, such as Promogran ®. There have been some advances made in the development of new antimicrobial dressings and they have been summarized by Hamm in a recent publication Antibacterial Dressings in Advances in Wound Care: Volume 1; Mary Anne Libert Inc.

Another strategy is to use synthetic protease inhibitors to decrease the activities of MMPs in the wound environment. Doxycycline, a member of the tetracycline family of antibiotics, is a moderately effective inhibitor of metalloproteinases, including MMPs and the TNFα converting enzyme TACE.

We have demonstrated a reduction in inflammatory cell infiltrate and extra-cellular matrix in chronic pressure ulcers treated with mg doxycycline twice daily. Low dose doxycycline 20mg, twice daily has been proven to be beneficial in other pathologic states such as periodontitis that are characterized by chronic, neutrophil-driven inflammation, and matrix destruction.

As previously described, endocrine hormones, such as insulin, glucocorticoids, and oestrogen, play important roles in regulating wound healing. Although there is no current therapy that specifically addresses the molecular deficits created by type I or type II diabetes inadequate insulin levels or insulin resistance , systemic insulin injections may improve the local wound microenvironment.

For patients receiving long-term corticosteroids, the use of vitamin A seems to facilitate wound healing. Studies are underway to determine the efficacy of topical oestrogen applications on skin aging. New technologies are being developed to help researchers better understand the complex microenvironment that exists in chronic wounds.

The test is highly sensitive and there is a rapid turn around time. The drawback is that PCR can only be used to identify known organisms and new unknown microbes will not be detected.

Bacterial biofilms are well known in other medical specialities to cause a variety of chronic pathologies including periodontal disease, cystic fibrosis, chronic otitis media and osteomyelitis and prosthetic graft infection. Bacteria and fungi contained within the biofilm matrix are highly tolerant to killing phagocytic inflammatory cells neutrophils and macrophages , antibodies, and exogenous antibiotics, antiseptics and disinfectants.

Several factors contribute to the increased tolerance of bacteria in biofilms to these agents, including reduced penetration of large proteins antibodies into the dense exopolymeric matrix, binding of oppositely charged molecules like antibiotics or cationic heavy metal ions silver ion by negatively charged components of the exopolymeric matrix, or neutralization of highly reactive chemicals like hypochlorous acid bleach by reaction with molecules comprising the exopolymeric matrix.

These factors contribute to make biofilms extremely difficult to kill and clear from chronic wounds. Furthermore, components of the biofilm matrix and products produced by bacteria in the biofilm stimulate chronic inflammation, which leads to persistently elevated levels of molecules like proteases and reactive oxygen species that kill wound cells and damage proteins that are essential for healing.

These assessments of bacteria and fungi in wound samples have unquestionably generated important data that have been used for decades to help select therapeutic regimens for patients and their wounds. In other words, standard clinical microbiology assays only culture planktonic bacterial and fungal species that are able capable of growing on agar media plates supplemented with general nutrients in air at 37ºC.

Thus, it is reasonable to assume that a more complete picture of different bacterial species aerobes, facultative anaerobes, and obligate anaerobes and fungal species in a particular wound should improve the ability to assess the microbial bioburden on individual wounds and to indicate what therapeutic strategies would be optimal for each wound.

Fortunately, in the last few years sophisticated laboratory research techniques have been developed that allow a more complete assessment of bacterial bioburden. These data suggest that many of the bacteria present in biofilms in a chronic wound may never be successfully cultured in the standard clinical micro-biology laboratory due to obligate cooperation with other bacteria that create unique environmental conditions in a polymicrobial community of bacteria in biofilms.

A second major concept recently reported by Wolcott and colleagues 55 showed that mature biofilms are rapidly re-established in chronic wounds following surgical debridement, on the time frame of 24 to 72 hours. This indicates that sharp debridement opens a time-dependent therapeutic window to prevent the re-establishment of mature biofilms that are highly tolerant to host inflammatory response or to exogenous antimicrobial agents.

Spectrum of Bacterial Bioburden in Wounds. Contamination and colonization of bacteria usually do not substantially retard healing whereas infection clearly impairs healing. The concept of critical colonization evolved to describe a condition where levels more The molecular environment of chronic wounds contains elevated levels of inflammatory cytokines and proteases, low levels of mitogenic activity, and cells that often respond poorly to growth factors compared to acute healing wounds.

As chronic wounds begin to heal, this molecular pattern shifts to one that resembles a healing wound. As more information is learned about the molecular and cellular profiles of healing and chronic wounds, new therapies will be developed that selectively correct the abnormal aspects of chronic wounds and promote healing of these costly clinical problems.

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Introduction Acute wounds normally heal in an orderly and efficient manner, and progress smoothly through the four distinct, but overlapping phases of wound healing: haemostasis , inflammation , proliferation and remodelling Figure In order to identify the differences inherent in chronic wounds that prevent healing, it is important to review the process of healing in normal wounds FIGURE Phases of Acute Wound Healing Haemostasis Haemostasis occurs immediately following an injury.

FIGURE TABLE Inflammation Inflammation , the next stage of wound healing occurs within the first 24 hours after injury and can last for up to 2 weeks in normal wounds and significantly longer in chronic non-healing wounds Figure Neutrophils Neutrophils are the first inflammatory cells to respond to the soluble mediators released by platelets and the coagulation cascade.

Macrophages Activated macrophages play pivotal roles in the regulation of healing, and the healing process does not proceed normally without macrophages. Proliferative phase The milestones during the proliferative phase include replacement of the provisional fibrin matrix with a new matrix of collagen fibers, proteoglycans, and fibronectin to restore the structure and function to the tissue.

Fibroblast migration Fibroblasts migrate into the wound in response to multiple soluble mediators released initially by platelets and later by macrophages Figure Collagen and extracellular matrix production The collagen, proteoglycans and other components that comprise granulation tissue are synthesized and deposited primarily by fibroblasts.

Angiogensis Damaged vasculature must be replaced to maintain tissue viability. Granulation Granulation tissue is a transitional replacement for normal dermis, which eventually matures into a scar during the remodelling phase of healing.

Epithelialization All dermal wounds heal by three basic mechanisms: contraction, connective tissue matrix deposition and epithelialization. Remodelling Remodelling is the final phase of the healing process in which the granulation tissue matures into scar and tissue tensile strength is increased Figure Summary of acute wound healing There are four phases of wound healing: Haemostasis — establishes the fibrin provisional wound matrix and platelets provide initial release of cytokines and growth factors in the wound.

Comparison of Acute and Chronic Wounds Normal and pathological responses to injury Pathological responses to injury can result in non-healing wounds ulcers , inadequately healing wounds dehiscence , or in excessively healing wounds hypertrophic scars and keloids. Biochemical differences in the molecular environments of healing and chronic wounds The healing process in chronic wounds is generally prolonged, incomplete and uncoordinated, resulting in a poor anatomic and functional outcome.

Biological differences in the response of chronic wound cells to growth factors The biochemical analyses of healing and chronic wound fluids and biopsies have suggested that there are important molecular differences in the wound environments.

From Bench to Bedside Role of endocrine hormones in the regulation of wound healing Classical endocrine hormones are molecules that are synthesized by specialized tissue and secreted into the blood stream which are then carried to distant target tissue where they interact with specific cellular receptor proteins and influence the expression of genes that ultimately regulate the physiological actions of the target cell.

Molecular basis of chronic non- healing wounds Conditions that promote chronic wounds are repeated trauma, foreign bodies, pressure necrosis, infection, ischemia, and tissue hypoxia. Chronic venous stasis ulcers Mechanisms involved in the creation and perpetuation of chronic wounds are varied and depend on the individual wounds.

Pressure ulcers Chronic wounds have also been demonstrated to have elevated matrix degrading enzymes and decreased levels of inhibitors for these enzymes. Future Concepts for the Treatment of Chronic Wounds Although the aetiologies and the physical characteristics for the various types of chronic wounds are different, there is a common trend in their biochemical profiles.

Bacterial biofilms in chronic wounds Bacterial biofilms are well known in other medical specialities to cause a variety of chronic pathologies including periodontal disease, cystic fibrosis, chronic otitis media and osteomyelitis and prosthetic graft infection.

Conclusion The molecular environment of chronic wounds contains elevated levels of inflammatory cytokines and proteases, low levels of mitogenic activity, and cells that often respond poorly to growth factors compared to acute healing wounds.

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Within a day following injury, the inflammatory phase is initiated by neutrophils that attach to endothelial cells in the vessel walls surrounding the wound margination , change shape and move through the cell junctions diapedesis , more In addition to the growth factors and cytokines, a third important group of small regulatory proteins, listed in Table As their biochemical properties were established, it was recognized that the approximately 40 chemokines could be grouped into four major classes based on the pattern of cysteine residues located near the N-terminus.

In fact, there has been a recent trend to re-establish a more organized nomenclature system based on these four major classes. In general, chemokines have two primary functions: 1 they regulate the trafficking of leukocyte populations during normal health and development, and 2 they direct the recruitment and activation of neutrophils, lymphocytes, macro-phages, eosinophils and basophils during inflammation.

Neutrophils are the first inflammatory cells to respond to the soluble mediators released by platelets and the coagulation cascade. They serve as the first line of defense against infection by phagocytosing and killing bacteria, and by removing foreign materials and devitalized tissue.

During the process of extravasation of inflammatory cells into a wound, important interactions occur between adhesion molecules selectins, cell adhesion molecules CAMS and cadherins and receptors integrins that are associated with the plasma membranes of circulating leukocytes and vascular endothelial cells.

While rolling, leukocytes can become activated by chemoattractants cytokines, growth factors or bacterial products. After activation, leukocytes firmly adhere to endothelial cells as a result of the binding between their integrin receptors and ligands such as VCAM and ICAM that are expressed on activated endothelial cells.

Chemotactic signals present outside the venule then induce leukocytes to squeeze between endothelial cells of the venule and migrate into the wounded tissue using their integrin receptors to recognize and bind to extracellular matrix components. The inflammatory cells release elastase and collagenase to help them migrate through the endothelial cell basement membrane and to migrate into the extracellular matrix ECM at the site of the wound.

Neutrophils also produce and release inflammatory mediators such as TNF-α and IL-1 that further recruit and activate fibroblasts and epithelial cells.

After the neutrophils migrate into the wound site, they generate oxygen free radicals, which kill phagocytized bacteria, and they release high levels of proteases neutrophil elastase and neutrophil collagenase which remove components of the extracellular matrix that were damaged by the injury.

The persistent presence of bacteria in a wound may contribute to chronicity through continued recruitment of neutrophils and their release of proteases, cytokines and reactive oxygen species. Usually neutrophils are depleted in the wound after 2 to 3 days by the process of apoptosis, and they are replaced by tissue monocytes.

Activated macrophages play pivotal roles in the regulation of healing, and the healing process does not proceed normally without macrophages. Macrophages begin as circulating monocytes that are attracted to the wound site beginning about 24 hours after injury Figure They extravasate by the mechanisms described for neutrophils, and are stimulated to differentiate into activated tissue macrophages in response to chemokines, cytokines, growth factors and soluble fragments of extracellular matrix components produced by proteolytic degradation of collagen and fibronectin.

They patrol the wound area ingesting and killing bacteria, and removing devitalized tissue through the actions of secreted MMPs and elastase. Macrophages differ from neutrophils in their ability to more closely regulate the proteolytic destruction of wound tissue by secreting inhibitors for the proteases.

As important as their phagocytic role, macrophages also mediate the transition from the inflammatory phase to the proliferative phase of healing.

They release a wide variety of growth factors and cytokines including PDGF, TGF-β, TGF-α, FGF, IGF-1, TNFα, IL -1, and IL Some of these soluble mediators recruit and activate fibroblasts, which will then synthesize, deposit, and organize the new tissue matrix, while others promote angiogenesis.

The absence of neutrophils and a decrease in the number of macrophages in the wound is an indication that the inflammatory phase is nearing an end, and that the proliferative phase is beginning.

Proliferation Phase. Fixed tissue monocytes activate, move into the site of injury, transform into activated wound macrophages that kill bacteria, release proteases that remove denatured ECM, and secrete growth factors that stimulate fibroblasts, epidermal more The milestones during the proliferative phase include replacement of the provisional fibrin matrix with a new matrix of collagen fibers, proteoglycans, and fibronectin to restore the structure and function to the tissue.

Another important event in healing is angiogenesis, the in-growth of new capillaries to replace the previously damaged vessels and restore circulation.

Other significant events in this phase of healing are the formation of granulation tissue and epithelialization. Fibroblasts are the key cells in the proliferative phase of healing. Fibroblasts migrate into the wound in response to multiple soluble mediators released initially by platelets and later by macrophages Figure Fibroblast migration in the extracellular matrix depends on precise recognition and interaction with specific components of the matrix.

Fibroblasts in normal dermis are typically quiescent and sparsely distributed, whereas in the provisional matrix of the wound site and in the granulation tissue, they are quite active and numerous.

Their migration and accumulation in the wound site requires them to change their morphology and to produce and secrete proteases to clear a path for their movement from the ECM into the wound site. Fibroblasts begin moving by first binding to matrix components such as fibronectin, vitronectin and fibrin via their integrin receptors.

Integrin receptors attach to specific amino acid sequences such as R-G-D or arginine-glycine-aspartic acid or binding sites in these matrix components. While one end of the fibroblast remains bound to the matrix component the cell extends a cytoplasmic projection to find another binding site.

When the next site is found, the original site is released apparently by local protease activity , and the cell uses its cytoskeleton network of actin fibers to pull itself forward.

The direction of fibroblast movement is determined by the concentration gradient of chemotactic growth factors, cytokines and chemokines, and by the alignment of the fibrils in the ECM and provisional matrix.

Fibroblasts tend to migrate along these fibrils as opposed to across them. Fibroblasts secrete proteolytic enzymes locally to facilitate their forward motion through the matrix. The enzymes secreted by the fibroblasts include three types of MMPs, collagenase MMP-1 , gelatinases MMP-2 and MMP-9 which degrade gelatin substrates, and stromelysin MMP-3 which has multiple protein substrates in the ECM.

The collagen, proteoglycans and other components that comprise granulation tissue are synthesized and deposited primarily by fibroblasts.

PDGF and TGF-β are two of the most important growth factors that regulate fibroblast activity. PDGF, which predominantly originates from platelets and macro-phages, stimulates a number of fibroblast functions including proliferation, chemo-taxis, and collagenase expression.

TGF-β, also secreted by platelets and macrophages is considered to be the master control signal that regulates extracellular matrix deposition. Through the stimulation of gene transcription for collagen, proteoglycans and fibronectin, TGF-β increases the overall production of matrix proteins.

At the same time, TGF-β down-regulates the secretion of proteases responsible for matrix degradation and also stimulates synthesis of tissue inhibitor of metalloproteinases TIMP , to further inhibit break down of the matrix.

Recent data indicate that a new growth factor, named connective tissue growth factor CTGF , mediates many of the effects of TGF-β on the synthesis of extracellular matrix. Once the fibroblasts have migrated into the matrix they again change their morphology, settle down and begin to proliferate and to synthesize granulation tissue components including collagen, elastin and proteoglycans.

Fibroblasts attach to the cables of the provisional fibrin matrix and begin to produce collagen. At least 20 individual types of collagen have been identified to date.

Type III collagen is initially synthesized at high levels, along with other extracellular matrix proteins and proteoglycans. After transcription and processing of the collagen mRNA, it is attached to polyribosomes on the endoplasmic reticulum where the new collagen chains are produced.

During this process, there is an important step involving hydroxylation of proline and lysine residues. Three protein chains associate and begin to form the characteristic triple helical structure of the fibrillar collagen molecule, and the nascent chains undergo further modification by the process of glycosylation.

Hydroxyproline in collagen is important because it plays a major role in stabilizing the triple helical conformation of collagen molecules. Fully hydroxylated collagen has a higher melting temperature. When levels of hydroxyproline are low, for example in vitamin C-deficient conditions scurvy , the collagen triple helix has an altered structure and denatures unwinds much more rapidly and at lower temperatures.

To ensure optimal wound healing, wound care specialists should be sure patients are receiving good nutritional support with a diet with ample protein and vitamin C.

Finally, procollagen molecules are secreted into the extracellular space where they undergo further processing by proteolytic cleavage of the short, non-helical segments at the N-and C-termini. The collagen molecules then spontaneously associate in a head-to-tail and side-by-side arrangement forming collagen fibrils, which associate into larger bundles that form collagen fibers.

In the extra-cellular spaces an important enzyme, lysyl oxidase, acts on the collagen molecules to form stable, covalent, cross-links. As the collagen matures and becomes older, more and more of these intramolecular and intermolecular cross-links are placed in the molecules.

This important cross-linking step gives collagen its strength and stability, and the older the collagen the more cross-link formation has occurred.

Dermal collagen on a per weight basis approaches the tensile strength of steel. In normal tissue, it is a strong molecule and highly organized. In contrast, collagen fibers formed in scar tissue are much smaller and have a random appearance.

Scar tissue is always weaker and will break apart before the surrounding normal tissue. Damaged vasculature must be replaced to maintain tissue viability. The process of angiogenesis is stimulated by local factors of the microenvironment including low oxygen tension, low pH, and high lactate levels.

Many of these are produced by epidermal cells, fibroblasts, vascular endothelial cells and macrophages, and include bFGF, TGF-β, and VEGF. It is now recognized that oxygen levels in tissues directly regulate angiogenesis by interacting with oxygen sensing proteins that regulate transcription of angiogenic and anti-angiogenic genes.

For example, synthesis of VEGF by capillary endothelial cells is directly increased by hypoxia through the activation of the recently identified transcription factor, hypoxia-inducible factor HIF , which binds oxygen.

HIF-1 binds to specific DNA sequences and stimulates transcription of specific genes such as VEGF that promote angiogenesis. When oxygen levels in wound tissue increase, oxygen binds to HIF, leading to the destruction of HIF molecules in cells and decreased synthesis of angiogenic factors.

Regulation of angiogenesis involves both stimulatory factors like VEGF and anti-angiogenic factors like angiostatin, endostatin, thrombospondin, and pigment epithelium-derived factor PEDF. Binding of angiogenic factors causes endothelial cells of the capillaries adjacent to the devascularized site to begin to migrate into the matrix and then proliferate to form buds or sprouts.

Once again the migration of these cells into the matrix requires the local secretion of proteolytic enzymes, especially MMPs. As the tip of the sprouts extend from endothelial cells and encounter another sprout, they develop a cleft that subsequently becomes the lumen of the evolving vessel and complete a new vascular loop.

This process continues until the capillary system is sufficiently repaired and the tissue oxygenation and metabolic needs are met. It is these new capillary tuffs that give granulation tissue its characteristic bumpy or granular appearance.

Granulation tissue is a transitional replacement for normal dermis, which eventually matures into a scar during the remodelling phase of healing. It is characterized from unwounded dermis by an extremely dense network of blood vessels and capillaries, elevated cellular density of fibroblasts and macrophages and randomly organized collagen fibers.

It also has an elevated metabolic rate compared to normal dermis, which reflects the activity required for cellular migration and division and protein synthesis. All dermal wounds heal by three basic mechanisms: contraction, connective tissue matrix deposition and epithelialization.

Wounds that remain open heal by contraction; the interaction between cells and matrix results in movement of tissue toward the center of the wound. As previously described, matrix deposition is the process by which collagen, proteoglycans and attachment proteins are deposited to form a new extracellular matrix.

Epithelialization is the process where epithelial cells around the margin of the wound or in residual skin appendages such as hair follicles and sebaceous glands lose contact inhibition and by the process of epiboly begin to migrate into the wound area.

As migration proceeds, cells in the basal layers begin to proliferate to provide additional epithelial cells. Epithelialization is a multi-step process that involves epithelial cell detachment and change in their internal structure, migration, proliferation and differentiation.

Only the basal epithelial cells are capable of proliferation. These basal cells are normally attached to their neighboring cells by intercellular connectors called desmosomes and to the basement membrane by hemi-desmosomes. When growth factors such as epidermal growth factor EGF , keratinocyte growth factor KGF and TGF-α are released during the healing process, they bind to receptors on these epithelial cells and stimulate migration and proliferation.

The binding of the growth factors triggers the desmosomes and hemi-desmosomes to dissolve so the cells can detach in preparation for migration. Integrin receptors are then expressed and the normally cuboidal basal epithelial cells flatten in shape and begin to migrate as a monolayer over the newly deposited granulation tissue, following along collagen fibers.

Proliferation of the basal epithelial cells near the wound margin supply new cells to the advancing monolayer apron of cells cells that are actively migrating are incapable of proliferation. Epithelial cells in the leading edge of the monolayer produce and secrete proteolytic enzymes MMPs which enable the cells to penetrate scab, surface necrosis, or eschar.

Migration continues until the epithelial cells contact other advancing cells to form a confluent sheet. Once this contact has been made, the entire epithelial mono layer enters a proliferative mode and the stratified layers of the epidermis are re-established and begin to mature to restore barrier function.

TGF-β is one growth factor that can speed up the maturation differentiation and keratinization of the epidermal layers. The intercellular desmosomes and the hemi-desmosome attachments to the newly formed basement membrane are also re-established. Epithelialization is the clinical hallmark of healing but it is not the final event — remodelling of the granulation tissue is yet to occur.

Recent studies by Sen, et al. have demonstrated that under conditions of hypoxia, HIF-1alpha is stabilized which in turn induces the expression of specific micro RNAs that then down-regulate epithelial cell proliferation 1.

Therefore it appears that there are very complex mechanisms involved in the role of oxygen and hypoxia during the process of wound healing. Remodelling is the final phase of the healing process in which the granulation tissue matures into scar and tissue tensile strength is increased Figure The maturation of granulation tissue also involves a reduction in the number of capillaries via aggregation into larger vessels and a decrease in the amount of glycosaminoglycans and the water associated with the glycosaminoglycans GAGs and proteoglycans.

Cell density and metabolic activity in the granulation tissue decrease during maturation. Changes also occur in the type, amount, and organization of collagen, which enhance tensile strength. Initially, type III collagen was synthesized at high levels, but it becomes replaced by type I collagen, the dominant fibrillar collagen in skin.

Healed or repaired tissue is never as strong as normal tissues that have never been wounded. Tissue tensile strength is enhanced primarily by the reorganization of collagen fibers that were deposited randomly during granulation and increased covalent cross-linking of collagen molecules by the enzyme, lysyl oxidase, which is secreted into the ECM by fibroblasts.

Remodelling Phase. The initial, disorganized scar tissue is slowly replaced by a matrix that more closely resembles the organized ECM of normal skin.

Remodelling of the extracellular matrix proteins occurs through the actions of several different classes of proteolytic enzymes pro-duced by cells in the wound bed at different times during the healing process.

Two of the most important families are the matrix metalloproteinases MMPs Table Specific MMP proteases that are necessary for wound healing are the collagenases which degrade intact fibrillar collagen molecules , the gelatinases which degrade damaged fibrillar collagen molecules and the stromelysins which very effectively degrade proteoglycans.

An important serine protease is neutrophil elastase which can degrade almost all types of protein molecules. Under normal conditions, the destructive actions of the proteolytic enzymes are tightly regulated by specific enzyme inhibitors, which are also produced by cells in the wound bed.

The specific inhibitors of the MMPs are the tissue inhibitors of metalloproteinases TIMPs and specific inhibitors of serine protease are α1-protease inhibitor α1-PI and α2 macroglobulin.

Matrix metalloproteinases and tissue inhibitors of metalloproteinases. There are four phases of wound healing: Haemostasis — establishes the fibrin provisional wound matrix and platelets provide initial release of cytokines and growth factors in the wound.

Inflammation — mediated by neutrophils and macrophages which remove bacteria and denatured matrix components that retard healing, and are the second source of growth factors and cytokines.

Prolonged, elevated inflammation retards healing due to excessive levels of proteases and reactive oxygen that destroy essential factors. Proliferation — fibroblasts, supported by new capillaries, proliferate and synthesize disorganized ECM.

Basal epithelial cells proliferate and migrate over the granulation tissue to close the wound surface. Remodelling — fibroblast and capillary density decreases, and initial scar tissue is removed and replaced by ECM that is more similar to normal skin. ECM remodelling is the result of the balanced, regulated activity of proteases.

Cellular functions during the different phases of wound healing are regulated by key cytokines, chemokines and growth factors. Cell actions are also influenced by interaction with components of the ECM through their integrin receptors and adhesion molecules.

MMPs produced by epidermal cells, fibroblasts and vascular endothelial cells assist in migration of the cells, while proteolytic enzymes produced by neutrophils and macrophages remove denatured ECM components and assist in remodelling of initial scar tissue.

Pathological responses to injury can result in non-healing wounds ulcers , inadequately healing wounds dehiscence , or in excessively healing wounds hypertrophic scars and keloids. Normal repair is the response that re-establishes a functional equilibrium between scar formation and scar remodelling, and is the typical response that most humans experience following injury.

The pathological responses to tissue injury stand in sharp contrast to the normal repair response. In excessive healing there is too much deposition of connective tissue that results in altered structure, and thus, loss of function.

Fibrosis, strictures, adhesions, keloids, hypertrophic scars and contractures are examples of excessive healing. Contraction is part of the normal process of healing but if excessive, it becomes pathologic and is known as a contracture.

Deficient healing is the opposite of fibrosis. It occurs when there is insufficient deposition of connective tissue matrix and the tissue is weakened to the point where scars fall apart under minimal tension. Chronic non-healing ulcers are examples of severely deficient healing.

The healing process in chronic wounds is generally prolonged, incomplete and uncoordinated, resulting in a poor anatomic and functional outcome. Chronic, non-healing ulcers are a prime clinical example of the importance of the wound cytokine profile and the critical balance necessary for normal healing to proceed.

Since cytokines, growth factors, proteases, and endocrine hormones play key roles in regulating acute wound healing, it is reasonable to hypothesize that alterations in the actions of these molecules could contribute to the failure of wounds to heal normally.

Several methods are used to assess differences in molecular environments of healing and chronic wounds. Messenger ribonucleic acid mRNA and protein levels can be measured in homogenates of wound biopsies.

The proteins in wounds can be immunolocalized in histological sections of biopsies. Wound fluids collected from acute surgical wounds and chronic skin ulcers are used to analyze the molecular environment of healing and chronic wounds.

From these studies, several important concepts have emerged from the molecular analyses of acute and chronic wound environments. The first major concept to emerge from analysis of wound fluids is that the molecular environments of chronic wounds have reduced mitogenic activity compared to the environments of acute wounds.

In contrast, addition of fluids collected from chronic leg ulcers typically did not stimulate DNA synthesis of the cells in culture. Also, when acute and chronic wound fluids were combined the mitotic activity of acute wound fluids was inhibited.

Similar results were reported by several groups of investigators who also found that acute wound fluids promoted DNA synthesis while chronic wound fluids did not stimulate cell proliferation. The second major concept to emerge from wound fluid analysis is the elevated levels of pro-inflammatory cytokines observed in chronic wounds as compared to the molecular environment of acute wounds.

The ratios of two key inflammatory cytokines, TNFα and IL-1 β, and their natural inhibitors, P55 and IL-1 receptor antagonist, in mastectomy fluids were significantly higher in mastectomy wound fluids than in chronic wound fluids. Trengove and colleagues also reported high levels of the inflammatory cytokines IL-1, IL-6 and TNFα in fluids collected from venous ulcers of patients admitted to the hospital.

Harris and colleagues also found cytokine levels were generally higher in wound fluids from non-healing ulcers than healing ulcers. The third concept that emerged from wound fluid analysis was the elevated levels of protease activity in chronic wounds compared to acute wounds. More importantly, the levels of protease activity decrease in chronic venous ulcers two weeks after the ulcers begin to heal.

It is interesting to note that the major collagenase found in non-healing chronic pressure ulcers was MMP-8, the neutrophilderived collagenase. Thus, the persistent influx of neutrophils releasing MMP-8 and elastase appears to be a major underlying mechanism resulting in tissue and growth factor destruction and thus impaired healing.

This suggests that chronic inflammation must be decreased if pressure ulcers are to heal. Other classes of proteases also appear to be elevated in chronic wound fluids. It has been reported that fluids from skin graft donor sites or breast surgery patients contained intact α1-antitrypsin, a potent inhibitor of serine proteases, very low levels of neutrophil elastase activity, and intact fibronectin.

Chronic leg ulcers were also found to contain elevated MMP-2 and MMP-9, and that fibronectin degradation in chronic wounds was dependent on the relative levels of elastase, α1-proteinase inhibitor, and α2-macroglobulin.

Besides being implicated in degrading essential extracellular matrix components like fibronectin, proteases in chronic wound fluids also have been reported to degrade exogenous growth factors in vitro such as EGF, TGF-α, or PDGF.

Supporting this general concept of increased degradation of endogenous growth factors by proteases in chronic wounds, the average immunoreactive levels of some growth factors such as EGF, TGF-β and PDGF were found to be lower in chronic wound fluids than in acute wound fluids while PDGF-AB, TGF-α and IGF-1 were not lower.

In general, these results suggest that many chronic wounds contain elevated MMP and neutrophil elastase activities. The physiological implications of these data are that elevated protease activities in some chronic wounds may directly contribute to the failure of wounds to heal by degrading proteins which are necessary for wound healing such as extracellular matrix proteins, growth factors, their receptors and protease inhibitors.

Interestingly, Steed and colleagues 35 reported that extensive debridement of diabetic foot ulcers improved healing in patients treated with placebo or with recombinant human Pd GF Figure It is likely that frequent sharp debridement of diabetic ulcers helps to convert the detrimental molecular environment of a chronic wound into a pseudoacute wound molecular environment.

Frequency of Wound Debridement Correlates with Improved Healing. There was a strong correlation between the frequency of debridement and healing of chronic diabetic foot ulcers, supporting the concept that the abnormal cellular and molecular environment more The biochemical analyses of healing and chronic wound fluids and biopsies have suggested that there are important molecular differences in the wound environments.

However, these data only indicate part of the picture. The other essential component is the capacity of the wound cells to respond to cytokines and growth factors.

Interesting new data are emerging which suggest that fibroblasts in skin ulcers which have failed to heal for many years may not be capable of responding to growth factors and divide as fibroblasts in healing wounds.

Ågren and colleagues 36 reported that fibroblasts from chronic venous leg ulcers grew to lower density than fibroblasts from acute wounds from uninjured dermis. Also, fibroblasts from venous leg ulcers that had been present greater than three years grew more slowly and responded more poorly to PDGF than fibroblasts from venous ulcers that had been present for less than three years.

These results suggest that fibroblasts in ulcers of long duration may approach senescence and have a decreased response to exogenous growth factors. Classical endocrine hormones are molecules that are synthesized by specialized tissue and secreted into the blood stream which are then carried to distant target tissue where they interact with specific cellular receptor proteins and influence the expression of genes that ultimately regulate the physiological actions of the target cell.

Generally, epidermal cells are lost following any skin injury and they must be replaced by cell proliferation, which occurs largely in an epithelial zone back from the migrating epidermal tongue. It was previously assumed that these cells were the sole source of the wound granulation tissue that became activated by exposure to various growth factor signals and are triggered to proliferate and migrate in synchrony with the advancing epidermis.

By tracking fluorescent MSCs after intravenous injection into mice, several groups have reported a significant contribution by MSCs to the wound fibroblast population. Indeed, mice lacking the family transcription factor PU.

There are now a plethora of mouse studies designed to test individually the function of most immune cell lineages in the wound repair process. An alternative strategy for dampening the wound inflammatory response is to treat with known resolving factors, and this approach can also lead to reduced scarring.

In the clinic, it is presumed that the considerable vascular sprouting that occurs during any adult tissue repair process must play a pivotal role in healing, and there is much clinical anecdote that cutaneous innervation is important also.

Neither of these episodes has been extensively researched in the context of repair, but much is known about the development of vascular patterning during embryogenesis, where we know that endothelial cell sprouting is driven by vascular endothelial growth factor, and macrophages are important in these episodes.

Very little is known about the role of nerves during skin healing, although studies in the chick embryo suggest a reciprocal positive association between nerves and wound repair.

Much of what is known about the molecular and genetic aspects of skin wound healing has been gleaned from studies in mice, alongside some descriptive clinical observations. But the tissues of mouse and man are opaque and neither organism is particularly genetically tractable. These limitations have encouraged wound healing studies in Drosophila 44 and zebrafish.

Although the advancing wound epidermis is hidden beneath a scab in mouse wounds, the simpler fly epidermis can be live imaged, revealing dynamic cytoskeletal machineries, including lamellipodial and filopodial protrusions that enable fusion of epidermal wound edges together at the end of the healing process.

Translucent zebrafish larvae offer a phylogenetic step up from Drosophila , with greater parallels to our own repair machinery.

For example, rather than a single immune cell lineage, as in Drosophila , they have equivalents of all of our innate immune cells. Currently the most exciting insight from zebrafish studies of wound inflammation has been that reactive oxygen species like hydrogen peroxide can serve as immediate damage attractants to draw immune cells to wounds.

For example, neutrophils may be partly responsible for their own resolution by clearance of the attractants that first drew them to the wound.

Chronic wounds — diabetic foot ulcers, venous leg ulcers and pressure ulcers — do not adhere to the standard time course of cellular and molecular events that lead towards healing of a healthy acute wound Fig.

Where there should be wound granulation tissue there are vessels surrounded by fibrin cuffs presumed to be a response to venous hypertension , very little vessel sprouting and few, if any, myofibroblasts. There is generally a heavy inflammatory infiltrate, particularly of neutrophils, and these cells may be phenotypically different from their equivalents in a healing acute wound.

Chronic wound biology. Chronic wounds are often infected and exhibit a persistent aberrant inflammatory profile. Granulation tissue is defective and does not nurture healing, in part due to elevated matrix metalloproteases MMPs and poor fibroblast infiltration.

Neoangiogenesis is poor and fibrin cuffs restrict existing vessels, limiting the diffusion of oxygen through the wound, rendering the wound hypoxic. Frequently, hyperpigmentation as a consequence of melanocyte recruitment can occur at the wound site, and persist even after a chronic wound has successfully healed.

acute wounds are comparisons of healing vs. Chronic, persistent inflammation is a hallmark of most chronic wounds, 63 whereas during acute healing, the normal pathway is for resolution of the inflammatory response.

Of course, it is difficult to distinguish whether the continual open wound with exposure to microbes is causal of the chronic inflammation, or vice versa, or both.

For some immune cell lineages in some chronic wound scenarios, more may be better; for example, increased numbers of Langerhans cells in the epidermis of diabetic foot ulcers have been shown to associate with better healing outcome.

Even some of the useful functions of immune cells may be disrupted in chronic wounds, as it seems that their bactericidal and phagocytic activities may be reduced, in comparison with those in an acute wound setting.

With the growth of microbiome 16S ribosomal RNA sequencing opportunities, it is now possible to survey the full microbial flora of wounds, and early datasets are revealing some common genera between diabetic and venous leg ulcers, and significant differences also, whereas the microbial community across a sample of pressure ulcers appears to be the most variable.

The next investigative steps will need to include a similar characterization of fungal and viral infections in chronic wounds. It is also important to note that many models of pathological wound healing in mice, while accurately mirroring some of the systemic causes of impaired healing e.

There is a strong case to be made for improving such models by layering on some of these additional influencing factors so that data can be more usefully extrapolated to the clinic. This would certainly lead to development of more optimal models as reviewed by Nunan et al.

One of the mysteries in the field of tissue regeneration and repair is the heterogeneity among diverse organisms: some animals, including axolotls, can perfectly regenerate injured tissues and organs as complex as limbs, whereas others, like humans, replace damaged tissue with a connective tissue characterized by densely bundled orientated collagen fibrils called a scar.

The degree of fibrosis after damage varies across organs and tissues and between individuals. In human skin, two types of scarring following injury are distinguished: hypertrophic scars and keloids Fig. Aesthetically disturbing hypertrophic scars develop after surgery or from other trauma, particularly burns.

Keloids differ from hypertrophic scars in that they extend beyond the margins of the original tissue damage, and they do not regress spontaneously hypertrophic scars generally partially regress within 6 months. Excessive fibrosis. Hypertrophic scars have excessive collagen deposition, leading to a raised surface that partially resolves over time.

In contrast, keloid scars have thicker collagen bundles, extend beyond the original wound margin and rarely regress. Contractile myofibroblasts are prevalent in hypertrophic scarring but all but are absent in keloid tissue. Keloids can also be characterized by occluded blood vessels.

Both hypertrophic scars and keloids are major therapeutic challenges for surgeons and dermatologists. In order to aid advancement of wound healing research in directions that will lead to benefits in the clinic, we need a good dialogue between clinicians and basic scientists.

There follows just a few of the key unmet needs that might be worthy of research and provide clues as to prognostics and therapeutics for chronic wounds and for scarring.

We know that almost all chronic wounds begin as a small cut or abrasion, and almost certainly begin the repair process as a normal acute wound. At some stage they stall, but of course this is likely to be some days or weeks or even months before the patient presents at the clinic.

Unfortunately, we have little understanding of the time or stage in the normal cycle when stalling happens, and this may be crucial in developing therapeutics to reverse the failed process. There is a clear correlation between chronic wound duration and healing efficacy, 77 but more precise biomarkers to indicate key stages in the normal repair process would certainly be useful here and might also serve as prognostic indicators.

It is now well understood that innate immune cells exhibit various phenotypes or activation states that can be either very antimicrobial or more dedicated towards nurturing of repairing tissue by their release of growth factors and cytokines.

Learning how to manipulate or reprogramme the inflammatory response so it is most effective at staving off infection, and then able to switch to repair mode, and finally to resolve in a timely fashion to avoid the chronic inflammatory phenotype so common in persistent chronic wounds, would provide superb therapeutic tools.

It is generally believed that aspects of the acute wound inflammatory response drive scar formation at the time when skin wound healing is occurring — but can inflammation or its downstream consequences be modulated in ways that allow efficient healing but reduce scarring? Much is known about the cellular and molecular basis of normal skin healing, but there are still avenues of research left to unravel that will guide us towards better prognostic indicators and better therapeutics for the various skin wound healing pathologies reviewed above.

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J Pediatr Surg ; 20 : — Martin P , D'Souza D , Martin J et al. However, by necessity, repair leads to a rapid solution to injury and thus to scarring. Another important consideration is that most of the mechanisms of wound repair that have evolved are aimed at addressing acute tissue injury and Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'.

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Teleologically and from an evolutionary standpoint, the process of repair for higher animals needed to be rapid, economical from an energy standpoint, and allow for the immediate survival of the organism. However, by necessity, repair leads to a rapid solution to injury and thus to scarring.

Another important consideration is that most of the mechanisms of wound repair that have evolved are aimed at addressing acute tissue injury and Your Access profile is currently affiliated with '[InstitutionA]' and is in the process of switching affiliations to '[InstitutionB]'.

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Home Books Fitzpatrick's Dermatology in General Medicine, 8e. Previous Chapter. Next Chapter. Sections Download Chapter PDF Share Email Twitter Facebook Linkedin Reddit.

AMA Citation Falanga V, Iwamoto S. Chapter Mechanisms of Wound Repair, Wound Healing, and Wound Dressing. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K.

Goldsmith L. Lowell A. Goldsmith, et al. Fitzpatrick's Dermatology in General Medicine, 8e. The McGraw-Hill Companies; Accessed February 14, Relevant comorbidities, medications, and lifestyle factors include:.

While acute wounds typically follow the normal healing process of hemostasis, inflammation, proliferative tissue regrowth, and tissue strengthening through remodeling, chronic wounds tend to progress through the healing process at a slower pace.

Healing of a chronic wound may arrest for several weeks in one of the four phases—most commonly the inflammatory phase. There are several known factors that affect the mechanism of chronic wound healing.

These factors include: the presence of inflammatory cytokines or growth factors, infection at the wound site, formation of a biofilm over the surface of the wound, hypoxia often associated with cardiovascular, pulmonary, and vascular diseases , and a nutrient-poor diet. Once a wound has healed and begun the scarring process, the American Academy of Dermatology recommends applying petroleum jelly to the wound site to minimize dehydration of the scar and surrounding tissue, as well as applying sunscreen to the site daily to reduce hyperpigmentation associated with scar tissue.

As the elderly population rises, the need for wound care physicians will continue to grow appreciably. Vohra provides wound care services to over skilled nursing facilities SNFs across the United States and serves as a leading informational source for providers, emerging research, and novel therapies in the field of wound care.

As the leader in post-acute wound care, Vohra provides both bedside and telemedicine wound care treatment and management solutions to nurses , physicians , Skilled Nursing Facilities and patients.

Physicians considering a career in wound care are invited to explore our open opportunities. The Vohra Home Patient Care Program allows physicians to provide telehealth services for patients with both acute and chronic wounds , such as pressure ulcers, diabetic foot wounds, and venous ulcers.

This advanced telemedicine platform gives patients and home health caregivers the opportunity to readily access physician consultations to discuss any and all aspects of their treatment.

Learn more about how Vohra is setting the standard in the new world of healthcare. An application and server upgrade for the Marketing DB is scheduled for Dec 11 th between 6AM — 6PM EST Saturday.

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English Español Deutsch. Select your workplace Skilled Nursing Facility Home Health Agency Other Workplace. How did you hear about us? Referral Email Another website Search engine Social media Other. Username or Email Address. Remember Me. Skip to content The complicated mechanism of wound healing occurs in four phases: hemostasis, inflammation, proliferation, and remodelling.

Hemostasis Hemostasis is the first stage in wound healing that can last for two days. Inflammation The second phase of wound healing is called the Inflammatory Phase. Proliferation Phase three of wound healing, the Proliferative Phase, focuses on filling and covering the wound.

Remodeling Scar tissue formation characterizes the final Remodeling Phase also known as Maturation. The four phases of wound healing The complicated mechanism of wound healing occurs in four phases: hemostasis, inflammation, proliferation, and remodeling. Infected wound healing stages Chronic wounds do not follow the standard progression of wound healing seen in acute wounds , and instead tend to arrest temporarily in one of the wound healing phases most commonly the inflammation phase.

Factors that affect wound healing There are several factors that may impair the wound healing process, including: the pre-existing integrity of the wounded skin due to age or medical treatments, comorbidities, medications, infection, hydration state, nutritional status, lifestyle habits, and pre- and post-operative care if surgery has occurred.

Diabetes: A common complication associated with diabetes is peripheral neuropathy leading to foot ulceration. An additional complication is peripheral ischemia secondary to peripheral artery disease.

Both complications affect the proliferative phase of healing and lead to the overall slowing of wound healing. Obesity: Obesity is associated with an increased risk of ischemia and inadequate tissue oxygenation, which may lead to slowed wound healing or necrosis. Necrosis: Unplanned tissue death is another factor that may impede wound healing, requiring debridement to remove the affected tissue surgically before healing can proceed.

Poor nutrition: Malnutrition seen frequently in elderly patients , specifically inadequate protein intake, can lead to decreased blood vessel formation, collagen production, and fibroblast proliferation, which ultimately slows the wound healing process. NSAIDs non-steroidal anti-inflammatory drugs : The mechanism of pain reduction by NSAIDs occurs through the inhibition of PGE2, an inflammation mediator.

NSAIDs are known to slow wound healing through the halting of angiogenesis. NSAIDs also increase scar formation, particularly if used during the proliferative phase.

Steroids: The anti-inflammatory and immunosuppressive effects of steroids can hinder wound healing by decreasing fibroblast proliferation and collagen production.

Radiation therapy: Ionizing radiation beams can damage epithelial cells as they pass through to targeted tissues, causing skin tissue breakdown and slowed healing of existing and new wounds. Chemotherapy: Chemotherapeutic agents affect wound healing by delaying the inflammatory phase of healing and decreasing collagen production.

Smoking: Cigarette smoking, specifically the use of nicotine, affects blood flow by causing vasoconstriction. Alcohol: Alcohol intake is often associated with poor nutritional habits, which may result in decreased immune function. In addition, alcohol may impair wound healing by decreasing angiogenesis and collagen formation, leading to weaker scar tissue formation and an overall slower healing process.

Wound healing may also be positively impacted by the addition of certain supplements such as zinc and vitamin C. How chronic and acute wounds heal While acute wounds typically follow the normal healing process of hemostasis, inflammation, proliferative tissue regrowth, and tissue strengthening through remodeling, chronic wounds tend to progress through the healing process at a slower pace.

Vohra Wound Physicians is the forefront of management and treatment of chronic and acute wounds As the elderly population rises, the need for wound care physicians will continue to grow appreciably.

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