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The properties of hyaluronan and its role in wound healing

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Irene Anderson, BSc (Hons), DPSN, RN.

Lecturer, Tissue Viability, Department of Post-registration Nursing, University of Hertfordshire, Hatfield

Hyaluronan (HA) is a polysaccharide common to most species, including bacteria and mammals (Chen and Abatangelo, 1999). It presents as a viscous gel and is found in many sites in the human body, such as the vitreous body of the eye, skin and soft tissue such as synovial fluid (Laurent, 1989).

Hyaluronan (HA) is a polysaccharide common to most species, including bacteria and mammals (Chen and Abatangelo, 1999). It presents as a viscous gel and is found in many sites in the human body, such as the vitreous body of the eye, skin and soft tissue such as synovial fluid (Laurent, 1989).

This paper will consider the role of HA in wound healing.

Difficult-to-heal chronic wounds
Recalcitrant chronic wounds present a professional challenge and incur considerable financial costs for the NHS, as well as personal costs for patients and their families. The use of bioactive materials such as HA for these wounds has attracted attention. Recent work is beginning to examine the cost-effectiveness of using products with a high unit cost when measured against the progression to healing of wounds that present clinical challenges.

There is speculation that our increased understanding of the healing wound has produced few therapeutic benefits (Slavin, 1999), although 'much current work is targeted at defining the chronic wound environment and developing bioactive therapies that may redirect the healing process from chronicity to healing' (Moore, 1999). There is a clinical need to find a better way of managing chronic wounds, a problem that is likely to increase as the population ages (Graham, 1998).

Hyaluronan
Hyaluronan is a polysaccharide made up of a linear chain of N-acetyl glucosamine - glucuronic acid repeated many thousands of times (Calvin, 1998) and known as a glycosaminoglycan (GAG). The terms hyaluronic acid or sodium hyaluronate are often seen in the literature but it is accepted that 'hyaluronan' (HA) should generally be used, as polysaccharides should end with '-an' (Laurent, 1989). Other endings indicate acid and salt forms of the molecule. The dressing developed from this glycosaminoglycan is Hyalofill (ConvaTec Ltd).

Although HA has been known about for many years, and there have been many studies on its use in wounds, it has proved unwieldy to handle because, as a natural substance in the body, it is a gel. As Hyalofill, the dressing forms a gel with the wound exudate and is degraded within 48 to 72 hours (Navsaria, 1999). Much of the work on wounds has necessitated the substance being injected into the wounded area. Early in the 1990s a way was discovered of binding the substance with benzyl alcohol, a process of esterification, which rendered it manageable as a dressing without losing its identity (Snyder, 1999). The benzyl alcohol is broken down and excreted (Benedetti et al, 1994). Much of the research so far has been on animal models, but human studies are beginning to emerge. HA is a viscous substance that acts as a lubricant of joints as well as individual cells (Tortora and Grabowski, 2000). It may have a role in tissue hydration, as it is a very absorbent molecule (King et al, 1991).

HA is a large (macro) molecule that is present in and identical in every species (Chen and Abatangelo, 1999). It forms part of the extracellular matrix as a major component of ground substance, giving structure for other GAGs and proteoglycans (Bertolami, 1984). In wound healing the GAGs provide a temporary structure in the early stages of the wound (Gill, 1998). The temporary structure is replaced, as the wound matures, by the addition of protein molecules - proteoglycans, and collagen (King et al, 1991).

As granulation tissue matures the HA is degraded and, as the levels fall, more protein molecules are produced. The proteins bind to the HA to become proteoglycans and continue the healing process to build up tissue resilience (Calvin, 1998). HA molecules are able to absorb up to 3000 times their own weight in water. HA therefore has an important role as a hydrating agent for tissue (Snyder, 1999). HA was first isolated from the vitreous humour in 1934 (Laurent, 1989). It is found in virtually all tissue and fluid in the body with the highest concentrations in synovial fluid, the umbilical cord, the eye's vitreous body, and in skin, which has around 15g in the adult (Fraser and Laurent, 1989). It has a high daily turnover (Weigel et al, 1988). HA for exogenous use is commonly isolated from rooster combs (Benedetti et al, 1994).

Fetal tissue has a very high level of HA and wounds in fetuses heal by regeneration rather than repair. High levels of HA are thought to be instrumental in scarless healing by facilitating the movement and proliferation of fibroblasts, and by regulating the production and type of collagen (Desai, 1997). In the adult wound, the HA levels peak at around three days whereas, in the fetus, the levels are high for around three weeks (Longaker et al, 1991). The authors speculated that the addition of HA to wounds might mimic the fetal situation. Sadly, thus far, this has not proved to be the case (Devlin, 1994).

HA in wound healing - HA is known to be a structural and regulatory molecule influencing cell motility, phagocytosis and angiogenesis (Weigel et al, 1988). It also acts as a free radical scavenger and as an antioxidant (Chen and Abatangelo, 1999). Free radicals are highly unstable and can be destructive to nearby molecules (Tortora and Grabowski, 2000). The scavenging action may be particularly important in the skin's defence against solar radiation, and in the wound environment against degrading enzymes (Chen and Abatangelo, 1999).

The amount of HA in the body is variable and rises in response to early wound healing. It enhances motility of cells such as lymphocytes, inflammatory and connective tissue cells, by binding to receptors on them such as CD44 and the receptor for HA-mediated motility (RHAMM). The HA and the receptors bind and then separate, enabling the cells to move along in a 'wave form' (Calvin, 1998). Heparan sulphate and fibronectin interact with HA to help to weaken the attachments in this process. The viscosity of HA physically regulates this mobility, in response to the requirements of the wound (Davidson et al, 1994).

King et al (1991) speculated, but came to no definite conclusions, whether HA exerted direct action on cell proliferation and migration, or that by hydrating the environment, it ensured moist wound-healing conditions.

The action of HA is apparent very early in the wounding process. It has been demonstrated that HA levels rise at the time of wounding and the molecules bind to the fibrin in the clot (Weigel et al, 1988). The action is to make the clot swell and become more porous, facilitating cell migration into the matrix, to provide physical support. Cells from the periphery of the wound migrate in. In this way, the monocytes, macrophages and neutrophils are attracted to, and are able to proliferate in, the area and begin their phagocytic process (Mazzione et al, 1986).

Some cells secrete hyaluronidase to degrade HA. As this degradation takes place, the resulting fragments act on endothelial cells to stimulate angiogenesis. This could be a direct action, as there are HA receptors on endothelial cells (West and Kumar, 1989a), or it could be indirect, via angiogenic growth factor (West and Kumar, 1989b). The HA angiogenic effect takes place only on specific cells and depends on the HA chain being a certain length or molecular weight (West and Kumar, 1989a). The hyaluronidase reduces the viscosity of the HA and allows the expansion of the new blood vessels. As the HA becomes less viscous, it facilitates the motility and proliferation of macrophages and fibroblasts, and in turn collagen deposition. The resultant tissue swelling allows more space for cell activity (Mazzione et al, 1986).

Research into HA - Navsaria et al (1998) presented histological slides of the angiogenic response on porcine wounds treated with HA. The comparator was paraffin gauze and the wounds were being treated before keratinocyte grafting. The histological appearance of the angiogenic response showed a mature dermis with defined Rete ridges. Electron microscopy showed collagen fibres parallel to the epidermis while the control exhibited fewer collagen bundles and a more immature appearance. The authors concluded that exogenous HA applied to dermal beds as a pre-treatment would increase the 'take rate' of tissue replacement. HA was also found to be useful in burns, as neutrophil function is often impaired in these patients. The HA was delivered subcutaneously and stimulated neutrophil activity. Although not in dressing form it demonstrated the stimulatory action already determined in the laboratory (Arturson, 1985).

A French study demonstrated a decrease in wound size of 23% at seven days, with a 48% reduction in 21 days as opposed to 4.3% and 18% respectively, for a comparator group, in a trial among 50 patients with venous leg ulcers (Ortonne, 1996). The comparator group was treated with dextranomer, commonly used to treat venous leg ulcers in France. The HA was delivered in cream form on a gauze pad and both groups had daily dressing changes. There was a marked decrease in oedema in the HA group during this trial. Unfortunately, it was not stated what secondary dressing was used, or whether compression therapy was undertaken. This information would be useful, particularly if both groups received the same therapy. The effect of compression therapy on oedema reduction and healing rates of venous leg ulcers is well documented.

Hyalofill dressing
Hyalofill is an absorbent fibrous fleece that gels on interaction with wound exudate, creating a HA-rich environment on the wound bed. Baxter and Ballard (1998) presented four patients with recalcitrant wounds, complicated by underlying conditions such as Kaposi's sarcoma, osteomyelitis and diabetes. Although acknowledging their experiences were anecdotal, they illustrated types of recalcitrant wounds seen in their clinic and highlighted the cost benefits of enabling patients to be discharged from hospital, which fulfilled both cost-reduction needs and the patients' wishes.

The same authors (Ballard and Baxter, 1999) presented further patients and explained how Hyalofill was used as an instrument to 'kick start' the wound-healing process for two to three weeks, and then changed for a less costly dressing that would maximise the activity in the wound bed, by providing a moist wound environment. The rapid change evident with the use of Hyalofill may be because the action of HA is most prevalent at the inflammatory stage of wound healing. Withdrawing the dressing after this stage mimics the naturally reducing levels in the body in normal circumstances (Abatangelo et al, 1983). The dressing is designed to be left in situ for two to three days at a time, more often if the exudate level is high. The eight wounds were all clinical challenges and all had unique problems. There is no information on the previous therapies used on these patients, and whether all of the wounds continued to heal. It would be interesting to note if the 'kick-start' effect the researchers noted continued, or if HA has to be utilised more than once to continue progress.

The dressing is not yet available in the community, which may prove problematic if further treatment was required by these patients.

Hyalofill was initially introduced as a carrier agent for keratinocyte grafts (Harris et al, 1999) to ensure an active and well-vascularised wound bed, but is now actively promoted as a treatment modality in its own right. Sometimes the dressing is used through to healing.

Hollander et al (1999) described the treatment of a young man with Kaposi's sarcoma to the hands, as a result of advanced AIDS, and trauma. Despite exposed tendon and bone and an infection, the wounds healed and had a significant positive impact on the patient's quality of life, not least his wish to avoid surgery. The wound was re-dressed every two days initially, then every three days. It took three months to heal as the patient declined a skin graft. Within days of HA treatment beginning, increased vascularity was noticeable to the patient and his carer. This angiogenic response is characteristic of HA (West and Kumar, 1989a). There was no further infection, possibly due to increased activity of cells in the wound. Two skin grafts had previously failed due to infection. It would have been interesting to see whether the effect would have continued if the Hyalofill dressing had been changed to a moist wound dressing, and whether a skin graft would have taken at this time. There was undoubtedly renewed activity in the wound.

Hyalofill dressing is marketed for the treatment of wounds that are failing to respond to therapy (Ballard and Baxter, 1999). Many chronic wounds fall into this difficult-to-heal category, often because of their complexity. A chronic wound is one that appears to have a non-resolving inflammatory response that requires conversion to the proliferation stage of wound healing (Moore, 1999). These recalcitrant wounds cause considerable challenges to patients, carers and health-care professionals.

Wound healing in diabetes
People with diabetes have less efficient degradation and remodelling of the extracellular matrix and fibronectin, with a resulting increase in the rigidity of the basement membrane, which limits vascular dilatation. There can be a poor inflammatory response due to lowered fibroblast activity, and therefore lower collagen synthesis. There is also thought to be an increase in free radical production (Silhi, 1998). Current knowledge about the action of HA may indicate the usefulness of such a dressing in these circumstances, particularly by reducing the viscosity and rigidity of the wound environment. In a study of patients with diabetic foot wounds, improved wound healing was found, including in those wounds complicated by sinus (Foster et al, 1999). Little information is presented on previous treatments or specific details of healing rates.

Diabetes in humans induces a thickening in the capillary basement membrane, making it more difficult for cells to permeate. There is a need for increased levels of oxygen due to an increased metabolic rate. Insufficient levels can result not only in tissue hypoxia but decreased collagen production and bactericidal mechanisms. People with diabetes are prone to higher levels of free radical activity, and are therefore more prone to the damaging effects these have on the micro-vascular system (Silhi, 1998). Topical application of HA in diabetic patients may be less a question of replacing levels than maximising existing cell activity (Senior, 2000).

It has been said that, in situations where the healing process has come to a halt, progress may be made by creating a disturbance in the wound bed (Silver, 1984). It could be argued that Hyalofill is doing just that.

The future
The management of recalcitrant wounds is challenging for experienced teams in problem wound management, where many treatment modalities may have already been tried. As more evidence becomes available on the use of HA in such wounds, there may be an opportunity for centres of expertise in the UK and Europe to pool resources and identify common complicating factors. This may make randomised clinical trials more realistic.

Dealey (1998) describes difficulties recruiting patients for trials and acknowledges the usefulness of case studies, albeit with the ultimate aim of at least a multi-centred trial. This may become easier as more specialist clinics evolve.

The universal usefulness of the randomised-controlled trial has been questioned (Harding, 2000). Case studies and small-scale evaluations can be among a variety of sources used to build a bigger picture. This approach may be more relevant in recalcitrant wounds due to lack of common factors for a large trial. Nelson (2000) confirms that some cases can be so unusual and include myriad conditions that it would be difficult to find others with the same list. Patients with conditions that lead to recalcitrant wounds are often excluded from controlled trials for dressings.

Conclusion
Moore (1999) is positive about the benefits of bioactive materials. The article concentrates on growth factors; each may appear beneficial in its own right, but needs to perform as an interaction with others, and be delivered at its correct time in the healing process. While growth factors can take a lot of the credit for wound healing, HA appears to have a facilitating role and perhaps simply maximises what is there already. 'Effective repair is dependent on the integrated activities of cells, regulatory molecules and structural molecules' (Hopkinson, 1992).

An increasingly aged population may result in larger numbers of patients with chronic, problem wounds, with financial implications for health services, and personal costs to patients and their families. Although the unit costs may be high for bioactive materials, the price may be justified if they reduce the numbers of problem wounds and the time to healing. However, if cost-effectiveness is to be achieved then the treatments must be applied selectively and only when other avenues have been explored.

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