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Wound healing and potential therapeutic options

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Andrew Kingsley

CNS Infection Control and Tissue Viability, Northern Devon NHS Trust

Wound healing is a complex process that involves interacting cells, cytokines, enzymes, carbohydrates and proteins in cascades and sequences that are linear in character but occur seemingly simultaneously across the wound bed as different areas progress at different speeds. The process can be divided into inflammation, proliferation and maturation phases (Cox, 1993).

Wound healing is a complex process that involves interacting cells, cytokines, enzymes, carbohydrates and proteins in cascades and sequences that are linear in character but occur seemingly simultaneously across the wound bed as different areas progress at different speeds. The process can be divided into inflammation, proliferation and maturation phases (Cox, 1993).

Stage one: the inflammatory phase
The inflammatory phase begins with haemostasis and lasts for approximately the first five days following the wound (Calvin, 1998), ending when fibroblasts become the main cellular entity. The main inflammatory cells are the leucocytes, specifically neutrophils and monocytes (monocytes become macrophages in the wound).

Following wounding, inflammation is the key non-specific immune response to prevent the establishment of infection. An individual's level of response depends on general health, nutritional state and the presence of any underlying disease (Keyworth, 2000). Inflammatory mediators are released from damaged cells, resident tissue macrophages and mast cells but perhaps largely from degranulating platelets (Ferguson and Leigh, 1998).

Platelets are a key component of the inflammatory stage. These cells originate in the bone marrow and leave on maturation with limited proliferative potential (Arai et al, 1990). They are filled with cytokines, which participate in the inflammatory phase of healing by directly influencing leucocytes:

- Platelet-derived growth factor (PDGF), which attracts leucocytes and fibroblasts into the wound (Deuel et al, 1982). PDGF works to promote both the deconstruction of damaged tissue and the reconstruction of new tissue

- Transforming growth factor-b, or TGF-b (Cox, 1993)

- Platelet-factor 4, or PF-4 (Deuel et al, 1991), which is chemotactic for neutrophils

- b-thromboglobulin, or b-THG (Slavin, 1999), which is also chemotactic for neutrophils.

Bleeding into the wound exposes platelets to damaged endothelium and collagen, which produces a sudden change in their behaviour leading to platelet aggregation, adhesion to injured vessel walls and degranulation (Rizza, 1992; Hopkinson, 1992). Alpha granules in platelets degranulate within seconds when activated by thrombin in the clotting cascade, discharging mediators for vasoconstriction, such as prostaglandin, leukotrienes (Deuel et al, 1991) and serotonin (Rizza, 1992), which assist haemostasis.

Once haemostasis is achieved, vasodilation and increased vascular permeability follows, stimulated by bradykinin, a by-product of the clotting cascade (Rizza, 1992), and the anaphyloxins, which are activated components of the complement cascade (Calvin, 1998).

The role of neutrophils - Neutrophils, which are derived from bone marrow, are also known as granulocytes because they contain granules full of cytotoxic agents (proteases and microbiocidal enzymes) that kill bacteria following phagocytosis (George, 1997; Slavin, 1999), which is their prime function. Neutrophils are drawn to the wound along with monocytes, but the former initially arrive in greater numbers (Calvin, 1998) because they are the most prevalent type of white blood cell in the peripheral circulation (Janeway and Travers, 1997). This leucocyte recruitment to the wound bed, already underway as a result of platelet products, is enhanced by other cytokines, extracellular matrix components, fibrin degradation products arising from plasmin activity on the blood clot, platelet-activating factor (PAF) from endothelial cells and other activated neutrophils, and bacterial cell-wall products (Clark, 1996; Riches, 1996; Parkin and Cohen, 2001). The chemotactic gradient produced by these substances induces the neutrophils to leave the circulation through spaces in the now permeable vascular endothelium (Parkin and Cohen, 2001). The activated neutrophils release elastase and collagenase to enable their access through the capillary basement membrane and into the wound (Schultz and Mast, 1998).

Once in the wound, neutrophils ingest and kill (phagocytose) bacteria by engulfing them into phagosomes. These are then combined with cytoplasmic granules to produce a phagolysosome. Within this structure the bacteria are destroyed by the action of the enzymes myeloperoxidase and lysozyme and by an oxygen-dependent respiratory burst that produces reactive oxygen species such as hydrogen peroxide, super oxide anion and oxygen- free radicals (Schultz, 2000). Phagocytosis is enhanced significantly by opsonisation of the bacteria with antibody or complement (Parkin and Cohen, 2001). Alternatively, neutrophils can release the contents of their granules in the direction of the opsonised-targeted bacterium (George, 1997). Because this process is non-specific, these products may cause damage to healthy tissue (Calvin, 1998). Neutrophils survive for about 24 hours when released from the bone marrow into the circulation (Slavin, 1999). Neutrophil infiltration of the wound bed peaks at 24 hours, declining over a few days (Slavin, 1996) but continues in bacterially contaminated wounds (Calvin, 1998).

Macrophages - Macrophages have many influences on wound healing, including:

- Phagocytosing damaged tissue and bacteria

- Producing chemotaxins for continuing white cell recruitment

- Releasing proteases that lyse necrotic material

- Making cytokines to regulate new tissue formation (Calvin, 1998) such as TGF-b, which is a chemotaxin for inflammatory-phase monocytes, neutrophils and lymphocytes and proliferative-phase fibroblasts (Moore, 1999; Slavin, 1999). TGF-b also has other properties (Box 1)

- Producing Interleukin-6 (IL-6), causing a pyrexia that both aids immune function by stimulating opsonisation of pathogens and hinders the reproduction of those pathogens (Johnston and Unsworth, 2001).

- The matrix metalloproteases (MMPs) released by macrophages and neutrophils assist clearance of damaged extracellular matrix, or ECM (Schultz and Mast, 1998; Schultz, 2000), which must occur prior to the rebuilding process in the proliferative stage.

Macrophages decrease in number at the end of the inflammatory stage through apoptosis (programmed cell death) and a reduced level of cytokines that govern their survival (Ferguson and Leigh, 1998), which in the normal wound occurs at approximately five days from wounding.

Lymphocytes - Lymphocytes are white cells of the specific immune system that is a slower but more accurate defence mechanism than that of the white cells of the innate response. These cells are differentiated into T (thymus maturing) and B (bone marrow maturing) cells with distinct functions. B cells produce antibodies to specific antigens, a process termed humoral immunity. T cells involved in cell mediated immunity divide into subsets that produce either lymphokines to stimulate complement activation, helper cells (CD4) to encourage B cell proliferation, CD8 cells to suppress the humoral response and cytotoxic cells to destroy foreign, tumour and infected cells (Keyworth, 2000). Both sets also produce memory cells for faster responses to invasion of the same antigens on subsequent occasions. Lymphocytes and macrophages become the predominant cell types in the wound at 24-48 hours (Lingen and Nickoloff, 2001). Endothelial cell expression of cytokines attracts lymphocytes (Ferguson and Leigh, 1998; Lingen and Nickoloff, 2001).

In summary, the inflammatory stage is divided into two stages: early, marked by neutrophil influx, and late, marked by macrophage and lymphocyte accumulation (Moore, 1999). Down regulation of the inflammatory stage may occur through a variety of mechanisms. Ineffective down regulation of the inflammatory stage will prevent movement into the reconstructive stage and thus is a cause of wound indolence.

Stage two: the proliferative phase
The dominant cell type of the proliferative stage, with most influence in the formation of fibrous tissue and production of the dermal matrix, is the fibroblast (Moulin, 1995). The exact origin of the fibroblast is unclear, but it is thought to be derived from the surrounding dermal elements (Slavin, 1996). The functions of fibroblasts are to form the new loose extracellular matrix that comprises collagens, elastin, glycoproteins, proteoglycans (Moulin, 1995) and glycosaminoglycans, or GAGs (Waldrop and Doughty, 2000). The healing process is characterised by an increase in fibroblast mitogenic activity and by synthesis of collagen and collagenase as the fibroblasts attempt to repair and remodel the ECM they synthesise (Postlethwaite et al, 1988).

The macrophages present in the wound release growth factors, including cytokines, which act as chemoattractants for the fibroblasts (Williamson and Harding, 2000). These include platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), tumour necrosis factor (TNF) and fibroblast growth factor, or FGF (Williamson and Harding, 2000).

Interleukins - The interleukin (IL) family is a group of multifunctional cytokines with wide-ranging effect in the wound healing process. Interleukin-1 (IL-1) is produced by epithelial cells (Dorlands, 1994), monocytes and macrophages (Postlethwaite et al, 1983) and stimulates biological activities in fibroblasts. Postlethwaite et al (1988) demonstrated and compared the effects of the two forms, IL-1a and IL-1b on various fibroblast functions. The study was conducted in vitro and data was presented to show that the major type of human IL-1 are able to modulate key fibroblast functions including the stimulation of growth and prostaglandin production as well as increased rates of collagen synthesis and release of collagenase. Futhermore, the authors showed from their data that the IL-1s were able to stimulate fibroblast synthesis of tissue inhibitor of metalloproteases (TIMPs). These inhibitors turn off the activity of the metalloproteases that are useful in the inflammation stage but can be detrimental in the proliferative stage.

The role of fibroblasts and collagen - Collagen synthesis by fibroblasts is an integral part of granulation tissue formation (Calvin, 1998) and is therefore critical to the process of wound repair (Waldrop and Doughty, 2000). New granulation tissue at the wound site is red, has a firm texture and is granular/grainy in appearance, hence the name (Bale et al, 2000). The granulation tissue is composed of a dense population of macrophages and fibroblasts characterised by an extensive network of new blood vessels surrounded by loose collagen, elastin and proteoglycans (Slavin, 1999; Schultz, 2000; Clark, 1996).

Collagen is the most abundant connective tissue protein (Postlethwaite, 1978). Type I and Type III are the most common collagens found in wound healing (Slavin, 1999), although at least 19 different types of collagen have been identified and characterised (Eckles et al, 1996). In wound healing, Type III collagen and fibronectin are initially deposited. Type III collagen is later replaced by Type I (Eckles et al, 1996). The final presentation of the collagen in the granulation tissue does not resemble that of a normal unwounded dermis, which has a basket-weave formation. Instead the collagen fibres at the wound site present in a fashion aligned parallel to the stress lines of the wound (Witte and Barbul, 1997). This different construction gives rise to the subtly different appearance of scar tissue, which is weaker than unwounded skin. The growth factors at the wound site are responsible for the regulation of the collagen synthesis by fibroblasts and there is a fine balance between the synthesis and degradation of the collagen (Slavin, 1999).

Wound contraction - Wound contraction is the process by which the edges of a wound move towards each other to reduce the size of a break in the continuity of the skin (Nedelec, 2000) and thus hasten closure. Following injury, revascularisation of the wound bed and redevelopment of the ECM is achieved through cell proliferation and the production of granulation tissue. Contraction is also an element of the proliferative phase of wound healing, although this is not a regenerative activity but one that occurs through the centripetal movement of the tissues surrounding the wound (Ehrlich and Rajaratnam, 1990). While it is accepted that contraction occurs in most mammals, the extent to which this takes place is dependent on an array of variables, including species (Cherry et al, 1994) and the size and position of the wound (Berry et al, 1998). For example, it is suggested that an injury in a loose skin fold will contract more than a wound in an area where skin tightly covers underlying structures (Ono et al, 1999).

Although the mechanisms that control contraction may be difficult to define, this dynamic phenomenon is worthy of the investigation it attracts because the impact of contraction on a wound may be dramatic. However, the effects of contraction are not always beneficial and problems may arise when contraction continues following epithelialisation. The influence of wound contraction on the formation of hypertrophic scars and contractures has been well documented (Stephens et al, 2001). These difficulties result in changes in body image and/or limited function of the damaged area.

Fibroblasts and wound contraction - The association between fibroblasts and wound contraction is unsurprising as, following the inflammatory phase of healing, these cells densely populate the wound environment. Fibroblasts perform essential functions, including the production of GAGs and collagen, elements of the ECM. These processes are regulated by growth factors, including PDGF and transforming growth factor, or TGF (Krishnamoorthy et al, 2001).

Contraction may have a remarkable impact on wound healing. The process can potentially reduce the surface area of a wound and speed its closure. Although there is still a way to go before contraction in normal wounds is understood, there are implications for the treatment of chronic cavity wounds, such as pressure ulcers, in which closure is delayed. Identification of the factors that stimulate the contraction and production of synthetic versions of such wounds may overcome problems experienced by patients. If contraction occurs to an extent that would lead to hypertrophic scarring, the use of a contraction inhibitor may prevent this, providing a more positive outcome for the patient. This situation may arise in the future provided research is continued now.

As already mentioned, the different processes of wound healing overlap. In surgical wounds, where there is minimal loss of tissue, epithelialisation occurs simultaneously with collagen synthesis, but in more open wounds a bed of moist granulation tissue must first be laid to facilitate epidermal migration (Waldrop and Doughty, 2000). Within 12 hours of wounding, the normally arranged epidermal cells at the wound edge undergo changes in shape and function: the living basal layers and those immediately above flatten and stop producing keratin before starting to divide and migrate in order to cover the break in the skin (Pollack, 1982). This process may be hidden from view in wounds that have scabbed surfaces produced by the clotting process, as the keratinocytes have to descend below the surface to migrate across granulation tissue. To achieve this, the keratinocytes must cut their way through the fibrin clot by releasing chemicals that culminate in fibrinolysis. These chemicals include tissue-type and urokinase-type plasminogen activators, which release plasmin from the abundantly present plasminogen in the clot, and matrix metalloprotease-1 (Mehendale and Martin, 2001).

In open wounds that are without this migratory barrier, the process of re-epithelialisation is quicker and is visible as a thin, silvery, pink layer around the edge of the granulation tissue. In partial thickness wounds re-epithelialisation may also be observed in islands regenerating from the remains of appendageal structures, such as hair follicles (Waldorf and Fewkes, 1995).

Keratinocyte movement - There are three main theories regarding the method of keratinocyte movement but no consensus on which is correct. These are: single-cell migration through crawling by the formation of pseudopods; leapfrogging, in which each cell moves two or three lengths, then stops and lets other cells stream over it; and cells gripping on to fibronectin in the wound bed in 'tractor-tread' mode (Waldorf and Fewkes, 1995; Waldrop and Doughty, 2000). Epidermal cells continue to migrate until they meet others doing the same from different directions, whereupon they link to each other by forming desmosomal attachments. Return to normal morphology and function follows, with the basal cells dividing and sending daughter cells vertically to begin to form the various layers present in normal epithelium (Pollack, 1982). The rapid proliferative burst that keratinocytes are capable of is valuable in rapid resurfacing, which is a tool to prevent further ingress of pathogens that might harm the host and as such is a non-specific immune response. Early closure also reduces the chances of hypertrophic scarring (Iocono et al, 1998).

As would be expected, a number of cytokines are involved in re-epithelialisation and are released in large quantities at the wound edge. These include epidermal growth factor (EGF), heparin-binding EGF (HB-EGF), TGF-a, TGF-b1, nerve growth factor (NGF) and keratinocyte growth factor, or KGF (Mehendale and Martin, 2001). EGF may increase epidermal cell lifespan in vitro and increases the cells' DNA and RNA content (Pollack, 1985). These factors variously come from platelets, macrophages, fibroblasts and keratinocytes (Waldrop and Doughty, 2000).

Stage three: maturation
The third stage is also known as remodelling because that is essentially what is happening below the newly formed epidermis. Granulation tissue that replaces the fibrin clot is matured into scar tissue (Iocono et al, 1998), which gradually pales, shrinks and thins. This process of remodelling is governed by fibroblasts and proteases in a balance between deposition and degradation. Early collagen fibrils are laid down in a haphazard arrangement and cross-linking is weak, resulting in a tensile strength only 5% the strength of normal undamaged skin at two weeks from wounding. Remodelling, which can take more than a year (Waldrop and Doughty, 2000), improves tensile strength to 80% that of normal skin, so scar tissue remains weaker than surrounding skin. Over time, water held in the proteoglycan ground substance is reabsorbed as the concentration of the proteoglycans is reduced. Collagen is gradually realigned into a parallel formation and the type of collagen changes from Type III to predominantly Type I (Waldorf and Fewkes, 1995), causing the fine collagen bundles to consolidate to form thicker fibres (Iocono et al, 1998). These activities are responsible for thinning and shrinking the scar, whereas paling is as a result of cessation of capillary outgrowth and blood-flow moderation as the level of metabolic activity declines (Iocono et al, 1998).

The epidermis of a scar is thinner than when the wound was newly closed but thicker than that of normal skin. Scars in wounds of full-thickness skin loss do not regenerate hair follicles, sweat glands or other dermal appendages (Iocono et al, 1998). Mature scar tissue contains fewer cells and blood vessels than does normal skin and has a different collagen construction (Pollack, 1982).

Relating theory to clinical practice
The developing knowledge on wound biology and growth factors suggests that there are potential therapeutic options that will influence clinical practice in the near future, enabled by cellular growth techniques and recombinant technology, which can provide the biological compounds in relevant quantities (Cox, 1993). Slavin (1996) suggests topical cytokine preparations might be employed to aid chemoattraction of relevant cells, cause cell division, promote production of further growth factors, stimulate angiogenesis and upregulate synthesis of matrix protein.

A problem to overcome before the promise derived predominantly from animal studies is delivered is that there are key differences between acute and chronic human wounds. Schultz and Mast (1998) outline chronic wounds as having low mitogenic activity, elevated inflammatory cytokines and proteases, and senescent cells. Understanding these differences allows therapeutic concepts to be tested for the chronic wound environment, because this is the area of greatest clinical need and offers the potential for greatest reward. After all, there is little to be gained by tampering with wounds that are progressing along a normal healing pathway.

Schultz (2000) likens the chronic wound to barren soil, in that its cells require preparation by adequate oxygenation and supply of nutrients so that they are able to respond to the application of a growth factor. Wound-bed preparation is an emerging concept discussed in a recent publication edited by Cherry et al (2000), which throws up potential clinical interventions required to remove obstacles to healing. These obstacles are dead and unhealthy tissue, infection, adverse biochemical and cellular factors (Harding, 2000) and exudate imbalance.

By using knowledge of the healing process and systematically adopting the wound-bed preparation concept, nurses and other clinicians should be enabled to focus their choice of dressing product and wound-care interventions on unblocking the barriers to the wound healing cascade in the complex non-healing wound. Some of these clinical interventions will continue to use accepted methodologies, such as sharp debridement, and principles such as moist wound healing as well as incorporating new approaches to address biochemical and cellular imbalances.

Given that most practitioners find detecting biochemical and cellular imbalances in the absence of bedside tests a matter of educated guessing, the most valuable practical approach would be to begin by controlling other visible barriers, such as excess exudate or necrotic tissue, and the invisible but clinically detectable problem of bacterial infection, before progressing to the novel therapies. In this way, cost-effective, readily available solutions can be tried to advance healing before resorting to complex, expensive methodologies, which should be reserved for the remaining few intransigent wounds.

The concept of wound-bed preparation suggests multiple interventions are probably necessary to effect our great leap forward in the area of indolent chronic-wound management, and this may be why the application of single recombinant growth factors to chronic wounds has not produced overly encouraging results so far (Moore, 1999).

- This paper is based on assignments submitted for the Postgraduate Diploma/MSc in Wound Healing and Tissue repair at University of Wales College of Medicine.

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