Clinical REVIEW Overcoming the challenge of overgranulation

Wound repair is a highly complex process. When wounds fail to heal, it is usually the absence of granulation which is the main issue. However, there are times when an overgrowth of tissue can lead to practical management issues. This article will look at the normal wound process and seek to identify why the development of ‘overgranulation’ occurs. It will identify potential management strategies and explain why the use of a steroid-impregnated tape (Haelan Tape®, Typharm) may be an appropriate option for management in this client group.

Alison McGrath

central tenets of wound management often represented graphically as a KEY WORDS has been to facilitate the proliferation linear process, there are in fact many of granulation tissue in the wound interconnected components which Healing through the regulation of wound bed influence the process of healing; many Overgranulation moisture and, when required, the of the cells and chemical prompts Hypergranulation provision of additional moisture in the involved in the wound healing process Topical steroid wound healing environment. This is have more than one function and widely accepted as an essential facet of may demonstrate altered states good wound care and a prerequisite to of expression depending on their eventual tissue repair. interaction with other elements. For example, are involved he mechanisms of wound repair However, while granulation occurs in the immune response to bacterial following are complex, but, in an orderly, if occasionally, slow ingress and removal of non-viable Tas further research is undertaken, manner in the majority of wounds, in debris, but also have a role within clinicians and researchers are developing others it can become disorganised the production of growth factors greater understanding, including how and resulting in the production of a responsible for tissue regeneration. why these mechanisms are disrupted in protruding mass of granular tissue, certain individuals. which appears to inhibit wound closure. For these reasons, it is unsurprising This ‘overgranulation’ can be unsightly that despite the large amount of Arguably, the publication of Winter’s and distressing to patients, as well as research that has been undertaken study on wound healing (1962) brought posing a management challenge into wound healing, there are still areas about one of the greatest changes to clinicians. which are not properly understood in wound management. The research (Russell, 2000). suggested that the maintenance of This article will look at the potential a moist wound healing environment causes of overgranulation, the methods The natural healing process brought about enhanced wound employed to manage it, focusing on an is frequently divided into four healing, with increased granulation and approach that appears to provide a interconnected stages: re-epithelialisation and improved practical solution. 8 quality. This was in marked contrast 8 Granulation to previous approaches to wound Normal wound healing 8 Epithelisation management in which dry wound To appreciate why overgranulation 8 Maturation. healing was advocated. Since the occurs, it is important to understand adoption of this approach, one of the how wound healing takes place in Inflammation normal circumstances. The healing of Inflammation is a vascular and cellular wounds is a complex physiological response designed to defend the body process, which is essential to re- against alien substances and to dispose Alison McGrath is a Tissue Viability Nurse, North establish the integrity and function of of non-viable tissue. This prepares Yorkshire and York PCT the body (Flanagan, 1996). Although an environment conducive to the

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formation of new tissue at the site of Granulation new framework, providing the oxygen injury. In acute injury, the inflammatory The construction of new tissue within a and nutrients necessary to fuel cellular response is predominantly limited to wound requires two processes — the proliferation. the area of tissue damage and resolves formation of a new vascular supply within three to five days (Hart, 2002). to transport the raw building blocks Eventually, stimulated needed for tissue repair, and the use of by growth factors differentiate into Following injury, blood constituents these materials to synthesise protein , which act like smooth leak into the surrounding tissues, chains into new tissue. muscle fibres and exert greater tension activating the coagulation cascade across the wound and result in wound (Kerstein, 1997). Activated platelets One of the most important cells contraction. Large deep wounds may become very sticky and adhere in this process is the dermal . take a considerable length of time to to form a platelet plug, which acts These migrate into the wound and contract and heal. Contraction could as a provisional haemostat. This is increase in numbers through mitosis. be responsible for 40–80% of wound strengthened by strands of polymerised Stimulated by growth factors released closure in wounds left to heal naturally fibrin. This clot limits blood loss and by macrophages in the wound, fibrils of (Irvin and Challopadhyay, 1978). provides a fibrinous migratory scaffold reticulin are laid throughout the wound, This explains the clinical significance for the movement of a variety of cells which are later converted to . of wound edge approximation with into the wound site. Even as collagen is laid down by the external devices such as suture material; mechanical closure of the wound On injury, damaged cells release Following injury, blood shortens the healing process and can inflammatory mediators such as achieve enhanced cosmesis by reducing prostaglandins and histamine from constituents leak into the need for significant contraction. mast cells. Serotonin may also be the surrounding tissues, released, resulting in vasodilation of activating the coagulation Epithelialisation existing blood vessels and increased cascade. Epithelial migration is initiated soon cell permeability. This is seen clinically after injury, as cells adjacent to the as erythema and localised oedema damaged area begin to divide and as fluid leaks into surrounding tissues. fibroblasts, collagenases and other move across the field of injury. In partial Vasodilation and increased vessel proteolytic enzymes remodel it. Matrix thickness wounds, these cells are found permeability enable extravasation of metalloproteinases (MMPs) are a group in hair follicles and sebaceous glands the , monocytes, and T and of enzymes which play an important as well as the neighbouring intact B lymphocytes into the tissues. These role in the proliferative phase of (Mercandetti and Cohen, are attracted into the wound within healing (Stephens and Thomas, 2002). 2005). hours of injury by the action of In particular, collagenase regulates the the mediators. balance between collagen synthesis In deeper wounds, lateral extension and lysis by facilitating the growth of of the epidermal keratinocytes across Wound cleansing is started by new and the re- the wound is the primary method of phagocytotic macrophages which absorption of the re-paving. These migrating keratinocytes arrive within 1–2 days, digesting the (ECM), the temporary filler which are delicate and require a moist fibrin and providing a defence against physically supports the newly-formed oxygen-rich environment if optimum . Macrophages and neutrophils blood vessels and granulation tissue proliferation and migration is to are essential for the transition from the characteristic of the proliferative be achieved. inflammatory to proliferative phase phase (Edwards al, 1987; Stephens and of healing. Thomas, 2002; Vuolo, 2010). In normal Numerous factors act as a stimulant wound healing the level of production to keratinocyte migration, such as There are also growth factors that (synthesis) is greater than destruction altered calcium levels, exposure to initiate the movement and proliferation (lysis), therefore, there is net gain in damaged extracellular matrix, loss of of fibroblasts, which in turn lay down collagen. As the process continues, contact inhibition, alterations in tension the structural protein and collagen for this balance is shifted until eventually within the epithelium and exposure to tissue repair (Kerstein, 1997; Morison et equilibrium is established. growth factors. al, 1997). Local tissue hypoxia acts as the Once activated, cells dissolve their The interleukins (cytokines) are primary stimulus for anchoring structures (these are known involved in inflammation and wound (Flanagan, 1997), along with the release as desmosomes and hemidemosomes) healing and affect local tissue by of angiogenic factors from macrophages (Santoro and Gaudino, 2005) and increasing tissue adhesion and attracting and platelets, and found in deposit proteins called integrins on T and B lymphocytes to the site of the fibrin scab. Endothelial cells in the filaments. These enable the cell the injury. form of capillary buds grow into the to ‘stick’ to new tissue. The cell flattens

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and forms projections (pseudopodia, This tissue is highly vascular with a biofilms. The presence of bacteria lamellipodia and filopodia), which dense network of blood vessels and within tissue further adds to exudate are used to drag the cell to its new capillaries. This means that it is often production and can offensive location. The keratinocytes gradually dark in colour, ranging from dark red odour, infection and delays in healing. move over the granulation tissue to bluish purple (Harris and Rolstad, under the level of the scab (if one has 1994; Johnson, 2007). Biopsy of the Wounds exhibiting overgranulation formed), and enzymes break down clot tissues usually reveals an overgrowth of have been found to be slower in and debris. fibroblasts and endothelial cells, with a healing. This chronicity makes them similar structure to healthy granulation more prone to infection (Nelsen, 1999) As the cells migrate, new tissue but in excess of that normally and subsequent wound deterioration. keratinocytes are formed behind this In addition, the presence of bacteria leading edge by the stimulation of may contribute to further abnormal growth factors. This process continues The formation of granulation. It has also been suggested until the advancing keratinocytes meet granulation tissue is a that by forcing regenerating wound their counterparts moving in from the central event during the borders apart, the overgranulation other direction, at which point contact proliferative phase of tissue may increase the risk of scar inhibition causes them to stop migrating tissue (Dunford, 1999). and reform anchor proteins which fix wound healing. the cell to the underlying surface. If overgranulation occurs in wounds around or near devices, the presence Maturation seen (Dunford, 1999; Semchyshyn, of raised tissue can offer a physical The newly-healed wound may be 2009). Generally, overgranulation barrier to device placement. For covered in epithelial tissue but the tissue is not painful as it contains little example, overgranulation around stoma disorganised collagen lacks strength. nerve tissue, however, if left untreated, wounds can prevent the close fitting During this final stage of healing, the innervation can occur which will of stoma flanges, gastrostomy tubes type III collagen that is prevalent during increase sensation. and tracheostomy tubes. This further proliferation is gradually replaced by complicates management, as exudate stronger type I collagen (Dealey, 1999). Effects of overgranulation and effluent is able to come into Collagen fibres are realigned along Although relatively minor in both intimate contact with the peristomal tension lines and cross-linked through prevalence and size, overgranulation skin leading to breakdown. a process of collagen synthesis and lysis can have a profound impact on healing (Lorenz and Longaker, 2003). and patient well-being, as well as Rollins (2000) reports that many resulting in frustration for clinicians. patients feel that clinicians trivialise the Redundant fibroblasts and impact of overgranulation. superfluous capillaries are removed by Granulation tissue is highly a process of . This stage can vascularised but lacks a protective Causes of overgranulation take up to two years to complete and epithelial layer — it therefore tends to The exact mechanism of over- generally results in a mature scar, which remain moist and is unable to withstand granulation is unknown. However, has up to 80% of the tensile strength even minor trauma. In an affected there may be a number of contributing seen in the pre-damaged tissues wound, overgranulation tissue will be mechanisms, which either in isolation (Mercandetti and Cohen, 2005). proud of the surrounding epithelium, or together, provide an environment making it prone to damage from in which the production of excessive Overgranulation contact (i.e. rubbing) with dressings and granulation tissue is likely to occur. The The formation of granulation tissue clothing. Similarly, leakage of haemo- low prevalence of overgranulation makes is central to the proliferative phase serous exudate can lead to painful it difficult to perform meaningful studies of wound healing (Romo et al, 2008). periwound maceration and soiling (in terms of patient population) from However, in some cases the formation and can require the prolonged use of which to draw conclusive evidence on of granulation tissue continues without protective and absorbent dressings. its cause and treatment (Nelsen, 1999). the migration of epithelial cells across Perhaps because of this, although it can the wound bed. As this occurs, the The moist wound surface of delay healing, overgranulation occupies a granular tissue increases to a level granulation tissue, combined with lower ranking in research priorities than higher than the surrounding healthy the excellent vascularisation that many other wound-related issues tissues. This forms areas of friable, provides oxygen and nutrients to the (Vuolo, 2010). irregular heaped tissues referred to tissues, provide an ideal environment as hypergranulation, overgranulation, to support the growth and migration The overwhelming opinion is that hypertrophic granulation, hyperplasia of of keratinocytes. However, this overgranulation is precipitated by granulation tissue or proud flesh (Harris environment is also ideal for bacterial an aberrant inflammatory response, and Rolstad, 1994; Young, 1995). colonisation and the formation of although the precipitating mechanisms

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for this may be diverse and are highly Mechanical/trauma The result of prolonged patient-dependent. In some circumstance it is necessary inflammation, whatever the cause, to leave a foreign material such as may be the formation of non-cellular There appear to be a number a gastrostomy tube, flange or metal extracellular matrix and fibres in of factors that could initiate a excess of what is required for wound overgranulation response: healing (Dunford, 1999). In addition, the 8 Infection/high bioburden The overwhelming opinion increased permeability of the capillary 8 Reaction to foreign bodies is that overgranulation is network leads to the formation of 8 Mechanical/trauma precipitated by an aberrant wound oedema. This may be amplified 8 Allergy/hypersensitivity. inflammatory response, by the use of occlusive dressings, which although the precipitating prevent the evaporation of excess moisture (Hampton, 2007). Falanga Infection/high bioburden mechanisms for this may Critical colonisation and localised, (1988) suggests that there may be links subclinical infection have also been be diverse and are highly between the use of occlusive dressings recognised as significant factors in patient-dependent. (such as hydrocolloids) and the prolonged wound healing (Edwards development of overgranulation. This and Harding, 2004; Warriner and appears to be supported by Vandeputte Burrell, 2005). This is frequently seen in orthopaedic pin in a wound to and Hoekstra (2006), who suggest that chronic, hard-to-heal wounds where a encourage the formation of an artificial it is the fluid within the overgranulated cyclical process is found in which the epithelialised track. Older, biological tissue which is the principle cause of bacterial load and interaction with the materials such as latex are associated the problem. host defences stimulate an immune with adverse reactions and an increased response, leading to increased levels risk of high bacterial colonisation. There may also be a relationship of proteases. These proteases interfere This is supported by Hanlon and between the proteolytic enzymes, with normal wound healing leading to Heximer (1994) who reported a higher matrix metalloproteinases and the wound chronicity. incidence of overgranulation in areas development of overgranulation. surrounding latex tubes than with Sussman and Bates-Jensen (2006) However, the failure of a wound other materials such as silicone. suggest that an imbalance of the to heal also results in an increased Therefore, more biocompatible normal collagen synthesis and lysis opportunity for organisms to colonise tube materials, such as polyurethane previously mentioned could result in it, further extending healing times. and silicone, are recommended the unchecked proliferation of collagen High levels of bacteria in the wound (Huddlestone et al, 1989). leading to hypergranulation formation. compete for nutrition and oxygen with the host tissues, and bacterially- However, even when newer Treatment options produced proteases are released which products are used, repeated trauma Little research has been carried out interfere with normal repair processes. through friction and traction on the into the treatment of overgranulation If the numbers of bacteria reach high wound can still lead to inflammatory and, thus, management regimens tend enough levels, or the host defences reactions (Hanlon and Heximer, 1994). to develop out of clinicians’ anecdotal are compromised, local and systemic Such irritation can be commonplace experience, which obviously varies infection can occur. in gastrostomy and tracheostomy considerably. To date, there is no site wounds and may account for the consensus on the best way to manage Reaction to foreign bodies frequency with which overgranulation these wounds. However, as with all The presence of foreign material is seen in these wounds. Vuolo (2010) wound issues, the implementation within a wound can lead to prolonged suggests that mechanical irritation of any management regimen should inflammation as the body seeks to and the development of subsequent be preceded by a thorough and overcome a perceived threat to tissue inflammation may also be the cause holistic assessment of the patient integrity. The decline of cotton wool of overgranulation in other wounds as and the presenting problems. Where as a cleansing material has seen a dressings rub on the wound interface. possible, the causative factors should reduction in fibres acting as a focus of be eliminated, or their impact on the inflammation in the wound. However, Allergy/hypersensitivity wound healing cascade minimised. For many less-informed patients and A number of wound products, such example, if localised inflammation is informal carers continue to use shedding as adhesives and some antimicrobial precipitated by repeated mechanical material as a method of coping with agents, have the potential to trigger an trauma from dressings and appliances, high levels of exudate. This can result in immune reaction in some susceptible it is important to ensure that these are significant amounts of debris being left individuals. This immune response acts correctly secured (Vuolo, 2010). in the wound margins. Unless removed, as a focus of continued inflammation this will act as a focus for a prolonged until the causative ingredient is Similarly, if the principle cause inflammatory response. removed. of overgranulation is poor moisture

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control and oedema, steps should be cause systemic effects if used over a overgranulation tissue, in vitro and in vivo taken to manage this. The use of higher wide area (Rollins, 2000; Dealey, 2005). studies of IL-1 have shown it to induce absorbency or less occlusive dressings Caustic preparations are no longer proliferation of fibroblasts, procollagen enable improved exudate management, recommended by many clinicians and type I and III synthesis and induce thereby preventing tissues becoming only tend to be used as a last resort collagenase secretion. saturated with fluid (Dunford, 1999). when all other options have failed The application of local pressure may (Griffiths et al, 2001; Hampton, 2007). These actions produce anti- also assist in forcing fluid out of the inflammatory and immunosuppressive tissues and so ‘flattening’ any raised Steroids effects and inhibit areas (Harris and Rolstead, 1994; In the absence of infection, the (Kragballe, 1989). However, they may Williams 1999; Rollins, 2000). This effect use of topical steroids should also impede healing, and products are may, in part, account for the success of be considered (Vuolo, 2010). often contraindicated for use on open foam-based dressing materials, however, These can effectively dampen the wounds (Young, 1995). Licensed usage in certain situations (for instance in inflammatory response and reduce should always be checked. wounds around stoma sites), this may the production of overgranulation be difficult to achieve. tissue (National Institute for Health Haelan® Tape and Clinical Excellence [NICE], 2004). One product that may be of Antimicrobial agents Corticosteroids modify the functions benefit due to its clinical effect, If the precipitating factor is the of the epidermal and dermal cells ease of use and suitability for many presence of high bacterial burden, and leukocytes that participate in overgranulated wounds, is Haelan® either as critical colonisation or local, proliferative and inflammatory skin Tape (Typharm). Haelan Tape is a sub-clinical wound infection, there is a . After passage through the cell protective, waterproof, self-adhesive need to redress the bacterial balance. membrane, corticosteroids react with polythene tape impregnated with 4ug/ Systemic antibiotics are effective in receptor proteins in the cytoplasm to cm2 fludroxycortide (flurandrenolone) reducing bacterial load but may be form a steroid-receptor complex. This (British Medical Association [BMA], associated with systemic complications complex moves into the nucleus, where Royal Pharmaceutical Society of Great and are not indicated for the treatment it binds to the cell’s deoxyribonucleic Britain, 2010). Fludroxycortide is a of colonisation and localised wound acid (DNA). DNA forms the ‘blue- fluorinated, synthetic, moderately infection (World Union of Wound print’ for the cell and so determines its potent corticosteroid. The product is Healing Societies [WUWHS], 2008; activity and function. However, DNA is recommended for the treatment of Best Practice Statement, 2010). locked within the cell nucleus. The cell recalcitrant dermatoses. Examples of therefore requires a messenger which this type of lesion include hypertrophic Topical antimicrobial products have can take the code from the nucleus to scarring, pyoderma gangrenosum and a more localised effect and may be the various organelles of the cell. This overgranulation tissue around effective at reducing bacterial burden function is undertaken by messenger stoma sites. without affecting systemic flora. This ribonucleic acid (mRNA). The binding makes them an effective tool in wound of the steroid-receptor complex to The tape is designed to allow the care, however, their use should be limited DNA changes the replication of mRNA, diffusion of the steroid to the affected to a 10–14-day period (WUWHS, 2008; (a process called ‘transcription’), altering area over a prolonged period of Best Practice Statement, 2010). In the the message given to the organelles of time. By occluding the treated area, management of overgranulation, topical the cell. penetration of the steroid is enhanced, antimicrobial products include povidone- increasing its local effect. It is also iodine, cadexomer-iodine, silver and As mRNA acts as a template for possible that the pressure exerted by honey-based dressings (Leak, 2002; protein synthesis, corticosteroids can the tape while in situ has a positive Hampton, 2007). either stimulate or inhibit the synthesis effect on reducing overgranulation of specific proteins. For example, tissue (Johnson, 2007). As with other Caustic preparations corticosteroids are known to stimulate topical steroids, the therapeutic effect Historically, caustic preparations the production of lipocortin, which of the product is primarily the result of have been used to ‘burn back’ inhibits the activity of phospholipase its anti-inflammatory activity. overgranulation tissue. The principle A2 (an enzyme that mediates the products used are silver nitrate inflammatory response), and inhibits The fludroxycortide contained in sticks but these have a number of mRNA responsible for interleukin-1 the tape binds to the glucocorticoid disadvantages, including damage to the (IL-1) formation. IL-1 is a cytokine receptors found in the cytoplasm surrounding skin and pain (Harris and which possesses a wide spectrum of of the cell, inhibiting prostaglandins Rolstad, 1999). They can also promote metabolic, and physiological activities, and leukotrienes, and stimulating tissue , which represents a and plays one of the central roles in the lipocortin-1 to escape to the further site of potential inflammation regulation of the immune responses. Of extracellular space. Lipocortin-1 (Nelson, 1999) and infection, and can particular relevance in the formation of binds to the leukocyte membrane

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receptors and inhibits various Case report inflammatory events initiated by Ms X was an 81-year-old woman who neutrophils, macrophages and was referred to the complex wound mastocytes (such as epithelial adhesion, clinic in May, 2008. She had a non- emigration, chemotaxis, phagocytosis, healing wound to her forearm following respiratory burst and the release of a fall over 20 weeks previously. She various inflammatory mediators). had initially been treated by her GP Additionally, the and the practice nurse, but despite is suppressed by a decrease in the the use of non-adherent impregnated function of the lymphatic system, a povidone-iodine and foam dressings, Figure 1. Wound with granulation tissue present. reduction in immunoglobulin and the wound had failed to progress to re- complement protein concentrations, epithelialisation. Referral to the plastic the precipitation of lymphocytopenia, surgery department was also being and interference with antigen-antibody considered, however, Ms X’s advanced binding (Reynolds and Parfitt, 1993). age made this option less appealing to both the patient and the care team. Although the use of topical steroid creams and ointments to manage Ms X’s wound was found to overgranulation has been alluded to by be painful. There was exuberant a number of authors (Dunford, 1999; granulation tissue present, which was Rollins, 2000), this can prove difficult bright red, soft and oedematous with a in the clinical environment due to the shiny appearance (Figure 1). There was additional moisture these products add no evidence of infection but the wound to the wound bed. However, because displayed signs of overgranulation Haelan Tape is steroid-impregnated, it and it was considered that control of is possible to cut it to fit the precise this tissue was necessary to enable shape of the lesion and place it around epithelial cover. Figure 2. After treatment with Haelan Tape the devices such as tubes and stoma sites. wound achieved full closure. This offers flexibility in practice It was decided to use Haelan® Tape (Layton, 2004). as this would achieve the wound care goals and be easy to administer. As well Conclusion Before application, Haelan Tape as providing the therapeutic effect of An intricate balance exists within the should be cut into a size that is 5mm the steroid in the tape-covered area, healing wound with many processes larger than the treatment area itself. the clinic thought that the exertion being modulated by interconnected Clinicians should ensure the treatment by the tape while in situ would have a chemical messengers. Therefore, it is area is dry and free from hair. The positive effect on the reduction of the not surprising that these processes corners of the tape should be trimmed overgranulation tissue. In addition, the can become disrupted, leading to off to minimise the risk of accidental tape would protect the wound area, wound healing anomalies, including the removal and the backing must be thus preventing damage from scratching production of overgranulation. While removed. Multiple strips of tape may be and other irritation. The tape was overgranulation is not life-threatening used to enable coverage of the cut to the desired shape and size to or life-limiting, it can seriously delay entire area. cover the wound and reapplied twice healing and result in distress for a week in clinic as, due to the location the patient. As with all steroid use, Haelan of the wound, Ms X was unable to Tape should not be used for long-term apply the product herself. Over a four- To date, there is no consensus on treatment. Depending on the nature week period, eight applications were the best way to treat this condition. of the lesion being treated, the tape administered. However, in the author’s opinion, can remain in situ for 12–24 hours, the use of an easy-to-apply steroid- or longer if clinical conditions dictate. The use of Haelan tape produced impregnated tape does appear to offer If used on the face or in children, an excellent clinical result (Figure 2). As clinicians a treatment that is effective courses should be limited to five days. well as eliminating pain, the protruding and well-tolerated. Wuk Cosmetics may be applied over the oedematous granular tissue resolved tape. If irritation or infection develops, and epithelial migration from the References wound borders produced a closed the tape should be discontinued and an Best Practice Statement (2010) The use of alternative therapy initiated. If there is wound. This had an immediate positive topical antiseptic/antimicrobial agents in no improvement observed within seven impact on Ms X’s wellbeing and surgical wound management. Wounds UK, Aberdeen days of use, treatment with Haelan Tape intervention (with all its potential risks BMA/Royal Pharmaceutical Society of Great should be discontinued. and associated costs) was avoided. Britain (2010) British National Formulary

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