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Wound healing--repair at the expense of function.

INTRODUCTION

Wound healing is an incredibly complex biological process that involves the activation and co-ordination of numerous cellular, matrix and biochemical processes. The ability to regulate these processes allows humans to rapidly regain tissue integrity following injury. Poorly regulated heating can Lead to morbidities such as chronic wounds, malignancies, keloids and hypertrophic scars.

In post-natal Life, healing occurs at the expense of function; in fetal Life, wounds are repaired by regeneration, Leaving no scar tissue. (1) Scars are mainly composed of disordered fibrous tissue with few cells and no resemblance to the original tissue being replaced. They are non-functional and only achieve about 70 percent strength. (2) This can cause significant impairment, for example following myocardial infarction where the presence of scar tissue causes heart failure and cardiac dysrhythmias. Lung fibrosis and Liver cirrhosis are also examples of the outcome of scar formation.

Wound healing occurs in three distinct, although overlapping, phases: inflammation, proliferation and maturation or remodelling (see Figure I, p24). In a healing wound, these phases occur more or Less sequentially. In a non-healing or Large wound, all three phases may occur at once in various parts of the wound.

PHASES OF WOUND HEALING

Inflammation

The inflammatory phase lasts between one and six days following injury (1,3) and is characterised by redness, heat and oedema at the wound margins (see photo, p26). The functions of this stage are to:

* Prevent further blood and fluid Loss.

* Protect against infection.

* Remove devitatised or dead tissue from the site of injury.

* Create an environment for the second phase of healing.

Following tissue injury, coagulation is initiated to prevent blood toss. The fibrin clot formed during coagulation fills the wound and provides a scaffold for the entry of inflammatory cells. Activation of platelets and the clotting cascade also trigger the release of cytokines, other inflammatory mediators such as bradykinin and histamine (from local mast cells) and the complement cascade. (4,5)

Complement is part of the innate immune system. The complement cascade has three roles: generation of pro-inflammatory mediators that attract neutrophils to the site of injury; production of opsonins--molecules that attach to invading pathogens and promote phagocytosis by neutrophils; and generation of membrane attack complexes (MACs) that pierce and destroy bacteria. (5)

Platelets, pathogens and debris from the injured tissue all trigger an acute inflammatory response. Bradykinin and histamine cause vasodilation of peripheral capillaries. Fluid and neutrophils move into the area of damage. Neutrophils utilise phagocytosis, release of proteolytic enzymes and generation of reactive oxygen species (ROS) to dear debris and pathogens from the wound site. (6)

The wound at this stage is hypoxic, due to compromised blood supply and high metabolic demand for oxygen. (3) Neutrophil function can be compromised if the wound is very hypoxic: neutrophils lose their bacterial-killing function at a pressure of oxygen less than 40 mmHg. (3) However, moderate hypoxia in the acute wound is apparently essential for the ordered progress of healing.

Neutrophils secrete a variety of cytokines that attract other inflammatory cells and trigger immune responses to the presence of micro-organisms. Neutrophils are the dominant cell population in the wound for the first 24 to 48 hours but are replaced by macrophages after this time.

Neutrophils undergo apoptosis (programmed cell death) and are incorporated into the wound eschar (scab), or phagocytosed by macrophages. During apoptosis, the neutrophil cell membrane remains intact so the cytotoxic chemicals inside are not released into the wound environment. If neutrophil death occurs due to necrosis (eg with prolonged ischaemia) or if there is reduced macrophage activity, the cytotoxic contents are released, further damage to the tissues occurs and inflammation is prolonged. (6)

Ingestion of neutrophils by macrophages appears to transform the macrophage from an inflammatory, phagocytic role to a reparative function. There is a change in the types of cytokines the macrophages produce. Acute inflammation resolves and there is a transition to the granulation phase. (6)

Proliferation

This phase is also referred to as granulation. It is recognisable by the appearance of red granular tissue in the wound cavity (see photo, p26). Four concurrent processes occur in the proliferation phase: fibroplasia, matrix deposition, neovascularisation and re-epithelialisation. (7)

Fibroplasia and matrix deposition: Fibroblasts divide and migrate from the wound margins, along the matrix scaffolding provided by the fibrin blood clot. Under the influence of cytokines secreted by macrophages, fibroblasts begin to proliferate and secrete components of the extracellular matrix (ECM).

ECM components are required to provide a scaffold for further cell migration. They are poorly organised initially and consist mainly of type III collagen, fibronectin and the glycosaminoglycans (GAGs), such as heparan sulphate and hyaluronic acid. Type I collagen appears tater in the granulation phase. Type III collagen has decreased strength compared with type I collagen, with only 20 percent of strength regained in the first three weeks of healing. (2) In the early stage of heating, the wound is prone to damage or dehiscence if healing by primary intention. (8)

The secretion of ECM components is reduced as the wound fills with granulation tissue. The majority of the fibroblasts undergo apoptosis and the remaining cells are involved in remodelling the ECM as the wound matures.

Fibroblasts require an adequate and ongoing supply of oxygen due to high metabolic demand; therefore angiogenesis is a vital co-requisite to fibroplasia and deposition of new ECM.

Neovascularisation: The growth of new blood vessels into the wound is a complex process. During angiogenesis, matrix metalloproteinases (MMPs) and other proteolytic enzymes digest the basement membrane of capillaries on the wound margin. This allows endothelial cells, directed by macrophage cytokines, to bud off from the capillary, begin proliferating and migrate into the wound along the new ECM scaffold. A separate process of vasculogenesis occurs where stem or progenitor cells are recruited from bone marrow or the circulation. These progenitor cells travel to the injury site and form new blood vessels. (9)

Capillary loops are formed that provide the healing wound with oxygen and nutrients. As the granulation phase is completed, these new blood vessels retract and endothelial cells undergo apoptosis. The mature scar is largely avascular and appears pale compared with surrounding tissue.

Re-epithelialisation: Re-epitheilaisation begins within hours following an injury. Keratinocytes (epithelial cells) recruited from wound margins, and any surviving epidermal structures such as hair follicles within the wound, begin to migrate into the wound.2 (See photo, p26). In the absence of a moist healing environment, keratinocytes cells migrate between the viable tissue and the dessicated scab, eventually leading to its separation.

Formation of the new epidermal layer requires that marginal keratinocytes cells detach from their neighbours and from the underlying dermis and move across the surface of the newly formed matrix. Cells behind the leading edge of keratinocytes begin to proliferate and mature. The wound takes on a pale pink appearance and, as the cells mature, the barrier function of the epithelium is restored.

During the final stages of proliferation, myofibroblasts appear in the wound. These are derived from fibroblasts and cause contraction of the wound edges. These cells contain actin filaments for contraction and have receptors on their membranes that allow them to link with neighbouring cells and with matrix proteins to exert mechanical force on the wound. (2) The activity of myofibroblasts extends well into the maturation phase of healing.

Failure to resolve the proliferation phase can lead to the generation of hypertrophic or keloid scars (see Figure 1). Ketoids are an over-proliferation of granulation tissue, extending beyond the edge of the original wound. They are composed mainly of type III (immature) or type I collagen in the mature keloid. Hypertrophic scars occur within the wound margin and tend to regress over time. (10)

Maturation

This begins two to three weeks after injury and continues for more than 12 months. As described above, the processes of proliferation wind down and cell numbers in the wound are reduced by apoptosis. Remaining fibroblasts continue to degrade and secrete collagen, as the ECM is remodelled to provide increased strength to the wound. Type III collagen is replaced by type I fibres. Unlike intact tissues, where type I collagen is normally found in ordered bundles arranged according to the direction of major tensile stresses, wound collagen is generally disordered. Maximum strength of the scar is attained at about 12 weeks, but remains only between 70 to 80 percent of uninjured tissue. (7)

The end result of this process is a scar composed mainly of ECM with relatively few cells and blood vessels. Scar tissue cannot perform the same functions as the tissue it replaced and, depending on Location and size of injury, this can cause morbidity and tong-term disability.

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REGENERATION VERSUS REPAIR

Loss of function during healing is a significant problem in wound care. An ability to regenerate tissue following injury is present in humans in foetal Life and in many Lower Life forms.

Amphibians have the ability to regenerate whole limbs, so Long as the nerve supply to the stump remains intact. In this process, mature cells around the injury de-differentiate to become non-specialised (stem or progenitor) cells that proliferate and reform the Limb by the same process that occurs during embryonic development. (1)

Mammals appear to have the mechanisms present to regenerate tissue but the rapid formation of fibrous scar tissue in healing inhibits this process. (1) Foetal wounds heat without scarfing, and this is thought to be due to a decreased inflammatory response in utero. (11) In particular, there is decreased tumour necrosis factor-beta (TNF-b). This is also reduced in the wounds of older adults and there is some evidence that this population heals in a more regenerative manner than younger adults, even though healing is slower. (11)

The ability to regenerate tissue rather than repair would be an enormous step forward in wound care. The complexity of cell interactions, cytokine effects and timing in both repair and regeneration makes regeneration seem an implausible goat. However, there is some encouraging research in progress in activating dormant progenitor cells, eg in the heart.

Bioengineered skin constructs using adult progenitor or stem cells incorporated into a biomatrix mimicking embryonic conditions are under development. These grafts, unlike autologous skin grafts, are temporary and act by generating appropriate cytokines and ECN components and attracting adult cells to the wound site, encouraging regeneration. (12,1,13)

CHRONIC WOUNDS

More than gO percent of non-healing wounds can be categorised as venous ulcers, pressure sores or diabetic ulcers. (19) The chronic wound is one that fails to progress through the phases of healing in an orderly or timely manner. (8) Chronic wounds can Lead to development of squamous cell carcinoma, although the exact mechanisms are not well understood.11 Generally, the chronic wound is arrested in the inflammatory phase and this may be due to a number of factors.

A chronic inflammatory response is considered to be due to persistent activation of the innate and acquired immune responses. Nacrophages continue to secrete pro-inflammatory cytokines that stimulate disordered collagen synthesis by fibroblasts, and recruit further macrophages and lymphocytes to the site, both of which cause more inflammatory effects including secretion of MMPs and ROS. (5) Conditions that may induce a prolonged inflammatory phase include tissue hypoxia or ischaemia, the presence of bacteria and the ischaemia/perfusion re-injury phenomenon. (19)

Hypoxia and ischaemia

Hypoxia and ischaemia are known to delay healing. Oxygen is required to form ATP and maintain adequate cellular function. Wounds are very metabolically active, with high numbers of cells, all undergoing division, growth, migration and secretion. Oxygen delivery must be adequate to meet this increased demand. Oxygen delivery to the wound is determined by: (3)

* Gas exchange at the Lungs.

* Concentration of haemoglobin in the blood.

* Cardiac output.

* Peripheral perfusion to affected area.

* Capillary density in the wound bed and edges.

Ischaemia has a profoundly detrimental effect on wound healing. Pressure that interrupts arterial flow to a wound should be identified and eliminated.

Peripheral vascular disease is a common underlying factor in diabetic foot ulcers--the macrovascutar complications of diabetes include atherosclerosis. However, a wound may be hypoxic without signs of overt ischaemia. Hypoxaemia, anaemia and heart failure are systemic conditions that can cause wound hypoxia and may require medical intervention.

Capillary density in the tissues immediately adjacent to a wound and the presence of excess fluid in the tissues (oedema) dictate the distance for diffusion of oxygen from blood to cells in the wound. Increased oedema or decreased capillary density will cause wound hypoxia.

Capillaries must be both present and well perfused. Impaired arterial flow as described above is one of the factors that may affect perfusion. Poor perfusion may also occur as a result of pressure, depletion of circulating blood volume (dehydration, haemorrhage), or activation of sympathetic vasoconstriction mechanisms. Vasoconstriction can occur as a result of stress, shock or cold.

Oedema can be addressed as part of the wound care process. Encouraging venous drainage through limb elevation, exercise and compression therapy for venous ulcers can decrease the distance between capillary bed and cells in the wound. Overt oedema is easily recognised but a wound in a prolonged inflammatory phase may have unidentified oedema present in the wound bed.

Bacteria and chronic wounds

Chronic wounds can be subject to both acute and chronic bacterial infections. An acute infection is aggressive and associated with tissue destruction (20) and increased signs of inflammation in the wound bed, and systemically, will be present. If treated with the correct antibiotics, the infection generally resolves within a short time.

Chronic wounds contain bacteria. The stages of bacteria[ presence are contamination, colonisation, critical colonisation and infection. (19,21) Traditionally, bacteria[ contamination and colonisation of a chronic wound have been regarded as relatively benign, only raising concern where there is invasion of underlying tissue and generation of an acute systemic inflammatory response. More recently there is recognition of the effect of prolonged bacteria[ presence in the wound and the generation of a chronic, localised inflammation that may be a significant underlying cause of impaired healing.

Sixty percent of chronic wounds contain biofilms, compared with only six percent of acute wounds. (21) Biofilms are communities of micro-organisms that form on biological or inert surfaces (eg indwelling urinary catheters). These communities develop protective matrices that are resistant to host immune responses and antimicrobial or antibiotic therapy.

Most biofilms are polymicrobial but all share the same basic features: (20)

(1) Attachment to a surface must occur before biofilm development. Initially this attachment is reversible, but as numbers increase, attachment becomes permanent and the bacteria within the film undergo differentiation. (21)

(2) The bacteria within the film secrete a protective matrix for protection against environmental insults (eg, dessication), host antibodies and leukocytes, and antimicrobial substances. This has a slimy character (think dental plaque--one of the earliest identified human biofilms).

(3) Bacteria communicate via quorum sensing--where molecular communication mechanisms cause changes in gene expression and differentiation of metabolic activity within the community.

(4) Biofilm can regenerate from remaining fragments if the main population is destroyed.

Attachment of bacteria begins within two to four hours of contamination (depending on the species of bacteria) and a fully mature biofilm can develop within two to four days. (21) Mature biofilms can be up to 500 times more resistant to antibiotics than free-floating bacteria, (22) and regeneration following disruption occurs within 24 hours. Fortunately, biofilms are more vulnerable to treatment during this regeneration phase.

Identification of the bacteria[ components of biofilms is not easy, and normal culture practices are largely ineffective. (20) Slough on the wound surface is not a biofilm, but the presence of slough is a possible indication of biofilm activity. (21)

Treatment of biofilms involves disruption of the film and then prevention of biofilm regeneration.

Mechanical or ultrasound debridement of the wound and cleansing of the wound surface are the most effective current therapies for biofilm disruption. (23,21) Prevention of regeneration involves use of occlusive dressings to prevent further wound contamination and the application of appropriately selected broad-spectrum antimicrobial agents, (22,21) such as silver, iodine and manuka honey.

Ischaemia reperfusion injury: The molecular and cellular events that occur once blood supply is restored following a period of ischaemia, can actually cause further damage to tissue. In chronic wounds there is a cycle of recurrent ischaemia and reperfusion that makes these unique, compared with other examples of the phenomenon such as stroke or myocardial infarction. (19) In venous leg ulcers, the Leg suffers a degree of ischaemia when in the dependent position (due to the consequences of venous hypertension) and reperfusion occurs with elevation of the leg. For pressure ulcers, repositioning of a patient alternately causes ischaemia and perfusion to compressed tissues.

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Ischaemia and lack of production of ATP causes cell swelling, membrane disruption and the generation of inflammatory cytokines. On reperfusion, leukocytes are recruited to the area and inflammation ensues. ROS are generated that overwhelm antioxidant mechanisms, and arteriolar, venular and capillary functions are impaired. Further damage to the ischaemic tissue occurs and a prolonged inflammatory state is generated. (19)

ENHANCING HEALING

For chronic wounds, the underlying aetiology must, if possible, be first identified and addressed. Regardless of underlying aetiology, there are a number of systemic and local factors that can be addressed to enhance wound healing in both acute and chronic wounds. The issues of hypoxia and bacterial burden have been addressed above. Nutrition, and the provision of an ideal wound environment need to be considered.

Nutrition and wound healing

Wounds are highly metabolically active and require energy, proteins and an array of macro and micronutrients in support. Malnutrition is recognised as impairing healing, although well-nourished patients can forgo food intake for a week preoperatively without any impairment to post-operative healing. (24)

Of particular importance is protein energy malnutrition, where the demands of the wound cannot be met. Trauma and surgery induce a catabolic state in the body, with breakdown of muscle to release amino acids and mobilisation of energy stores. These are utilised by the healing wound but the mechanisms underlying this ability to co-opt essential nutrients are unknown. (24) Inability to meet the wound requirements for energy and amino acids will result in Loss of Lean body mass.

Energy requirements of cells are met by glucose. Normally, dietary intake of carbohydrates is utilised for this purpose. If intake is inadequate to meet energy needs, fats stores and then protein are used to manufacture glucose. Energy requirements are increased further in the presence of wound infection, sepsis, major trauma, malignancy or chronic obstructive airways disease.

Proteins, or more specifically amino acids, are required in the wound for synthesis of ECM and cytokines, and for cell replication. Protein malnutrition has been associated with delayed angiogenesis, reduced fibroblast activity, impaired collagen formation and impaired immune function. (25) Proteins can be depleted through use as an energy source, oedema and wound exudate. Low levels of proteins will cause further oedema, thus impairing healing further. Arginine, in particular, seems to have an essential role in healing. (24,25)

Lipid stores can be used as an alternative energy source if carbohydrate supply is inadequate. There is some evidence to suggest that intake of omega-3 fatty acids may delay healing, presumably due to their anti-inflammatory actions. (24)

Micronutrients: Low Levels of vitamin C may impair immune function. Vitamin C is essential for synthesis and maturation of collagen. However, there is no evidence that increased vitamin C increases healing rates. In contrast, vitamin A appears to enhance healing even where there is no deficiency--it increases macrophage numbers in the wound and also the production of collagen. It is, however, toxic at high doses. (24) Vitamin E is an antioxidant and so may have a role in chronic wounds where ROS are impairing healing. In acute wounds, it is thought to delay healing through its anti-inflammatory mechanisms.

Zinc, copper and iron are at[ required for cell proliferation in the wound and matrix synthesis by the fibroblasts. (25) Zinc is also essential for MMP synthesis. While deficiencies of these elements may impair healing, there is no evidence that supplementation above normal levels will enhance wound heating. (24)

Assessment of risk of malnutrition: In both the hospital and community, the nurse should be aware of the risk of delayed healing associated with poor nutrition. The appearance of the patient, plus reports of toss of appetite, ability to access or prepare food, and amounts or type of food consumed daily, can form part of a subjective assessment that nurses can make in their encounters with patients. The presence of risk factors such as institutionalisation, older age, other disease processes, drug or alcohol use and multiple medications should also raise the possibility of malnutrition and lead to the implementation of more formal nutritional assessment and involvement of dieticians. (26)

The wound environment

Use of moist wound care products is now standard and the array available is vast. Choice of dressing is dictated by the type of wound, desired outcomes, wound exudate level and presence of infection. Addressing factors in the local wound environment with enhance healing: (12)

* Debridement of necrotic tissue.

* Removal of oedematous or excess wound fluid.

* Decreasing the bacteria[ burden of the wound.

* Provision of correct moisture balance.

The preparation of the wound bed for heating has received particular attention in recent years, using the acronym TIME to present the factors that require evaluation: (8)

T = tissue deficit or nonviable (necrotic, requiring debridement)

I = infection or inflammation

M = moisture imbalance (desiccation or excess fluid)

E = edge (undermined)

Beyond wound dressings, there is an increasing number of therapies available for treating chronic wounds. Evidence suggests that these therapies provide added benefits but, as with most wound care research, adequately constructed trials are required for definitive proof.

Negative pressure wound therapy

There is evidence that creating a sealed, negative pressure chamber around a wound enhances healing rates for large wounds and chronic ulcers.27 The mechanisms of action in heating for negative pressure are poorly understood but may include: (19,27,28)

(1.) Blood flow changes. Blood flow to surrounding tissue is increased but the wound itself is more hypoxic. This may stimulate angiogenesis and granulation tissue formation.

(2.) Removal of excess fluid. Oedema increases distance for diffusion from capillaries to the wound bed. Fluid removal may also decrease numbers of inflammatory cytokines and bacteria.

(3.) Microdeformation of cells in the wound bed. This could increase generation of ECM components and cell proliferation.

Negative pressure therapy should not be used in infected wounds or where there is increased risk of bleeding. (27)

Hyperbaric oxygen therapy

Increased pressure of oxygen arriving at the wound increases generation of ROS. This can enhance the phagocytic activity of white ceils in the wound bed. There is also evidence to suggest that neovascularisation and matrix generation are enhanced via a complex signalling pathway initiated during synthesis of ROS. (16,17) Risks associated with hyperbaric oxygen therapy include oxygen toxicity and the possibility of increased oxidative stress. (17)

Stem cell therapy

Stem cells are undifferentiated and so can theoretically be stimulated to develop into any cell type within the body. Progenitor cells are lines that are slightly more committed to a single cell type. Stem or progenitor ceils taken from bone marrow can be transplanted into wounds with some effect.

There is also the prospect of engineering skin substitutes using stem cells and, as described above, bioengineered skin constructs that stimulate regeneration. (9) This technology is still in the very early stages.

CONCLUSION

Wound care has moved beyond the application of the wound dressing to a more sophisticated assessment of aetiologies, wound condition and of cellular and molecular events. While most wounds heal without major intervention, non-healing wounds present significant challenges. An understanding of the physiology of wound healing can enhance delivery of care by providing a rationale for therapy choices.

Wound healing occurs wherever in the body there is an interruption to the integrity of the tissues. After surgery, myocardial infarction or superficial injury, all damaged tissues follow a similar pattern of healing: inflammation, granulation and maturation. The human body undergoes healing rather than regeneration so that structural integrity is regained as rapidly as possible but at the expense of function. For some wounds the process is arrested in the inflammatory stage and healing becomes prolonged. Chronic wounds create significant burdens on individuals and on the health care system.

This article examines current understanding of the processes of normal healing, the factors associated with delayed healing and modern approaches to wound care.

LEARNING OUTCOMES

After reading this article and completing the associated online learning activities, you should be able to:

* Describe the phases of wound healing.

* Outline key cellular and chemical components in wound healing.

* Discuss factors that influence heating.

* Describe the impact of biofilms on wound healing.

* Describe the rationale for current approaches to wound care.

* Outline emerging trends in the treatment of chronic wounds.

KEY MOLECULES IN WOUND HEALING

Cytokines Cytokines are proteins, or protein fragments, that attach to receptors on cell membranes

and alter cellular function. Abnormal cytokine activity has been associated with inflammatory, immune, autoimmune and neurodegenerative conditions, including asthma and type 1 diabetes mellitus. (14)

In wound heating, cytokines can be either pro-inflammatory or anti-inflammatory. They control cell proliferation (replication), cell migration, and the synthesis and secretion of extracellular matrix components and of other cytokines.

Platelets, neutrophils, macrophages, endothetial cells and fibroblasts secrete cytokines involved in wound heating. Secretion is triggered by the presence of pathogens or endotoxins, cellular or matrix debris and hypoxia or acidosis in the injured tissue.

Chemokines are smart cytokines that induce chemotaxis in cells--the movement of cells along a chemical concentration gradient. Chemokines are essential for cell recruitment into the wound.

Tumour necrosis factors (TNF), interleukins, interferons and growth factors--eg platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF)--are different types of cytokines.

The precise rotes of cytokines in wound heating are difficult to clarify because they have altered effects, depending on the cell they act on, the wound environment (degree of hypoxia or acidosis) and the presence of other cytokines. Cytokines can interact with each other as agonists (activators), antagonists (deactivators) and synergists (enhance the actions) of other cytokines. (14) So, although the application of topical growth factors (eg, becaplermin) to wounds has been an important development, it is not the universal panacea that was initially hoped. (15)

Reactive oxygen species (ROS)

Molecules of reactive oxygen such as hydrogen peroxide ([H.sub.2][O.sub.2]) and superoxide ([O.sub.2]-) are formed during cell respiration but are normally rapidly inactivated by antioxidant molecules. In phagocytic cells, such as macrophages and neutrophils, specialised enzyme pathways in the lysosomes generate ROS that are used to destroy phagocytosed bacteria.

ROS are highly reactive and, if free in the cell or extracellular matrix, will bond with structural proteins, lipids or polysaccharides and destroy them. ROS also trigger pathways that generate pro-inflammatory cytokines and MMPs. (11)

The formation of ROS by phagocytic cells requires a high level of oxygen. The enzyme that forms ROS in the lysosomes--NADPH-linked oxidase--is completely dependent on the presence of oxygen. (3) In the process of generating ROS, this enzyme also generates molecules that provide a chemical gradient to attract other white cells to the wound site. (16) Severe hypoxia in a wound may inhibit this process and impair defences against invading pathogens.

ROS and reactive nitrogen species (RNS) also increase recruitment and activation of stem/progenitor cells from bone marrow, that increase new brood vessel formation in the wound by vasculogenesis. (17)

Matrix metalloproteinases (MMPs)

Macrophages, endothetial cells, fibroblasts and keratinocytes secrete these zinc-containing enzymes. MMPs are essential to the heating process as they degrade the matrix scaffold to arrow cell migration through the wound. Secretion of MMPs is stimulated by pro-inflammatory cytokines that also down-regulate the secretion of MMP-inhibitors.11 MMPs, and related enzymes such as serine proteinases, also break down essential repair factors such as PDGF, so the unregulated expression of MMPs can prolong inflammation. Tissue-inhibitors of MMPs (TIMPs) are secreted to inactivate MMPs, and the balance between secretion of these and MMPs is essential for ordered heating. Dressings that bind to MMPs and remove them from the wound fluid have been demonstrated to increase heating rates in chronic venous ulcers. (18)

References:

(1) Gurtner, G. et al. (2008) Wound repair and regeneration. Nature; 453, pp314-321.

(2) Singer, A. & Clark, R. (1999) Cutaneous wound heating. The New England Journal of Medicine; 341:10, pp738-746.

(3) Schremi, S. et al. (2010) Oxygen in acute and chronic wound healing. British Journal of Dermatology; 163:2, pp257-268.

(4) Peerschke, E. et al. (2008) Platelet mediated complement activation. Advances in Experimental Medicine and Biology; 632, pp81-89.

(5) Ward, P. (2010) Acute and chronic inflammation. In Serhan, E., Ward, P. & Gilroy, D. (eds) Fundamentals of inflammation. New York: Cambridge University Press.

(6) Gilroy, D. (2010) Resolution of acute inflammation and wound healing. In Serhan, C., Ward, P. & Gilroy, D. (eds) Fundamentals of inflammation. New York: Cambridge University Press.

(7) Mercandetti, M. et al (2008) Wound healin9 and repair. Medscape Reference. http://emedicine.medscape.com/article/1298129-ovewiew#a1. Retrieved 6/6/11.

(8) Jones, V. et al. (2008) Acute and chronic wound healing. In Baranoski, S. & Ayello, E. (eds) Wound Cure Essentials: Practice principles (2nd ed). Ambler, PA: Lippincott Williams & Wilkins.

(9) Ko, S. et al. (2011) The role of stern ceils in cutaneous healing: What do we really know? Plastic end Reconstructive Surgery; 127(Suppl), pp10S-20S.

(10) Withelmi, B. et al. (2011) Widened and hypertrophic scar healing. Medscape Reference. http://emedicine.medscape.com/article/1298541-overview#aw2aab6b2blaa. Retrieved 6/6/11.

(11) Eming, S., Krieg, T. & Davidson, 3. (2007) Inflammation in wound repair: Molecular and cellular mechanisms. Journal of Investigative Dermatology; 127, pp514-525.

(12) Cherubino, M. et al. (2011) Adipose-derived stern cells for wound healing applications. Annuls of Plastic Surgery; 66, pp210-215.

(13) Lazic, T. & Falanga, V. (2011) Bioengineered skin constructs and their use in wound healing. Plastic and Reconstructive Surgery; 127(Suppl), pp75S-90S.

(14) Zidek, Z., Anzenbacker, P. & Kmonickova, E. (2009) Current status and challenges of cytokine pharmacology. British Journal of Pharmacology; 157:3, pp342-361.

(15) Fan K. et al. (2011) State of the art in topical wound-healing products. Plastic and Reconstructive Surgery; 127(Suppl), pp44S-59S.

(16) Hunt, T. (2010) Hyperbaric oxygen and wounds: A tale of two enzymes. European Wound Management Association Journal; 10:2, pp7-9.

(17) Thorn, S. (2011) Hyperbaric oxygen: Its mechanisms and efficacy. Plastic and Reconstructive Surgery; 127(Supp|), pp131S-141S.

(18) Raffetto, J. & Marston, W. (2011) Venous ulcers: What is new? Plastic and Reconstructive Surgery; 127(Suppl), pp279S-288S.

(19) Mustoe, T., O'Shaughnessy, K. & Kloeters, O. (2006) Chronic wound pathogenesis and current treatment strategies: A unifying hypothesis. Plastic and Reconstructive Surgery; 117(Suppl), pp35S-41S.

(20) Wolcott, R. & Dowd, S. (2011) The role of biofilms: Are we hitting the right target? Plastic and Reconstructive Surgery; 127(Supp;), pp28S-35S.

(21) Phillips, P. et al (2010) Biofilms made easy. Wounds International; 1:3. http://www.woundsinternational.com/article.php?issueid=303&contentid= 123&articLeid=8851. Retrieved 6/6/1.1.

(22) Cooper, R. & Okhiria, O. (2006) Biofilms, wound infection and the issue of control Wounds UK; 2:3, pp48-57.

(23) Ennis, W. et al. (2011) Current status of the use of modalities in wound care: Electrical stimulation and ultrasound therapy. Plastic and Reconstructive Surgery; 127(Suppl), pp93S-102S.

(24) Kavalukas, S. & Barbul, A. (2011) Nutrition and wound healing: An update. Plastic and Reconstructive Surgery; 127(Suppl), pp38S-43S.

(25) Demling, R. (2009) Nutrition, anabolism and the wound healing process: An overview. Eplasty; 9. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642618/. Retrieved 6/6/11.

(26) Casey, G. (2003) Nutritional support in wound healing. Nursing Standard; 17:23, pp55-58.

(27) Orgill, D. & Bayer, L. (201.1.) Update on negative-pressure wound therapy. Plastic and Reconstructive Surgery; 127(Suppl), pp105S-115S.

(28) Borgquist, O. et al (2011) The influence of low and high pressure levels during negative pressure wound therapy on wound contraction and fluid evacuation. Plastic and Reconstructive Surgery. 127:2, pp551-559.

Georgina Casey, RN, BSc, PGDipSci, MPhil (nursing), is the director of CPD4nurses.co.nz. She has an extensive background in nursing education and clinical experience in a wide variety of practice settings.
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Title Annotation:CONTINUING PROFESSIONAL DEVELOPMENT
Author:Casey, Georgina
Publication:Kai Tiaki: Nursing New Zealand
Article Type:Report
Geographic Code:8NEWZ
Date:Jul 1, 2011
Words:5347
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