Diabetic foot wounds and wound healing: a review – Review
* Diabetic foot wounds
* Abnormal wound healing
* Diabetic foot care
Diabetes can result in the development of several complications, including diabetic foot problems that can potentially lead to lower limb amputation. It is therefore essential that podiatrists understand the cause of diabetic foot ulceration, perform a risk assessment for all patients with diabetes and work as part of a multidisciplinary team. Diabetic foot complications must be treated rapidly and action should be coordinated to aid limb salvage. This article reviews the pathway to foot ulcer development, explains why such wounds are difficult to heal, outlines the role of the podiatrist in treating diabetic foot wounds, and looks at the wound healing products available.
Diabetes is believed to affect 2-4% of the general population (Kamal et al, 1996) and its incidence is increasing: by 2010 it is predicted that it will affect 239 million people worldwide (Mandrup-Poulson, 1998).
Diabetes can result in the development of several complications, including diabetic foot problems that can potentially lead to lower limb amputation. As many as 15% of people with diabetes will develop foot ulceration and its related complications (Rieber, 1996), and 3% will have a lower limb amputation (Boulton, 1997). People with diabetes have a 15-70 times greater risk of lower limb amputation than their counterparts without diabetes (Scottish Intercollegiate Guidelines Network, 1997), and 45-70% of all lower limb amputations are performed in people with diabetes (Philips and Dover, 1991).
The emotional and financial costs of diabetic foot disease are high and of obvious concern to the podiatrist, with much time and effort being dedicated to its prevention and treatment. An understanding of the cause of diabetic foot ulcerations and why these often become chronic is vital for the podiatry profession and others who are involved in diabetic foot care.
Definition of the ‘diabetic foot’
The term ‘diabetic foot’ is somewhat of a misnomer, as the condition has been defined as a group of syndromes that can involve neuropathy, ischaemia and infection (WHO, 1995). For descriptive purposes, the ‘diabetic foot’ can be considered as the neuropathic, ischaemic and neuroischaemic foot, with the neuropathic type being the most common (Thomson et al, 1991; Boulton, 1998; Gadsby and McInness, 1998; De et al, 2001).
Pathway to ulcer development
Research has shown neuropathy to be the predominant causative factor in the development of foot ulceration (Walters et al, 1992; Levin, 1995; Boulton, 1998; De et al, 2001). In combination with repeated minor trauma, it is the primary cause of diabetic foot ulceration, rather than ischaemia (Pecoraro et al, 1990).
Diabetic foot problems can develop extremely quickly, with tissue breakdown occurring rapidly and often complicated by infection (Edmonds et al, 1986). Once ulcers are formed, they are often slow to heal. Why should this be? Do people with diabetes have a slower healing rate, or are there cellular factors that are absent or distorted?
In recent years there has been a consensus that the wound healing process in diabetes contributes to the development of diabetic foot ulcers (Veves et al, 2000). The normal course of wound healing in people with diabetes appears to be hindered by many factors, including specific metabolic deficiencies and impaired physiological responses (Boulton, 1988; Pecoraro, 1991). This article examines some of the possible causes of delayed healing in diabetic foot ulcers.
Impairment of wound healing
Abnormal wound healing in people with diabetes is well recognised (Prakash et al, 1974; Goodson and Hunt, 1977, 1979; Seifter et al, 1981; Sternberg et al, 1985; Spanheimer, 1991, 1992; Bennet and Schultz, 1993; Bouter et al, 1993; Haralson, 1993). However, the exact mechanism by which healing occurs is not known (Reenstra et al, 2001). There is a dearth of evidence regarding many aspects of diabetic foot care, including prevention, treatment (Mason et al, I 999a,b; Kerr and Richardson, 2000; Hunt and Gerstein, 2001) and wound healing (Pecoraro et al, 1991).
It is doubtful that a single definitive cause of abnormal diabetic wound healing will ever be discovered; indeed, numerous causes have been postulated and a combination of factors would appear to be involved. Factors include cellular features, such as:
* Retardation of closure
* Delayed contraction, possibly because of retardation of the myofibroblast phenotype
* Effects on granulocytes
* Defects in chemotaxis
* Interference with collagen synthesis
* Effects on red blood cells
* Defective control of apoptotic cell death (Pearl and Kanat, 1988; Darby et al, 1997).
However, cellular factors alone are not responsible for the delays in ulcer healing. Other factors also play a role:
* The altered metabolism of carbohydrates, fats and proteins resulting from the absence or deficiency of insulin (Cooper, 1990).
* Hyperglycaemia leading to non-enzymatic glycosylation (Pearl and Kanat, 1988; McInnes, 2001).
* Osmotic diuresis leading to decreased perfusion and oxygenation (Terranova, 1991).
* Free radical production (Brownlee et al, 1984; Tooke, 1994).
Studies of diabetic wound healing
Much of the research on diabetic wounds has involved animals. Rodents are mainly used as they are inexpensive, easily housed and cared for, and tend to be more compliant than humans. Collagen deposition is a key feature in cutaneous repair in both rodents and humans, although rodents obviously do not accurately replicate the healing process that occurs in humans (Cohen and Mast, 1990). Research using human subjects is, however, fraught with difficulties, such as the difficulty in obtaining ethical approval and indeed volunteers with diabetes who would permit areas of their bodies to be wounded for research purposes.
Such difficulties have been recognised, and a model has been designed for the safe study of wounds in humans with high-risk conditions (Olerud et al, 1995).
Diabetic foot wounds vs control wounds
Olerud et al (1995) made small, identical wounds on the lower limbs of people with diabetes or with peripheral vascular disease who were awaiting lower limb amputation. An age-matched, healthy control group was used for comparison. A large number of individual wounds (309) were excised, and examined by two examiners to reduce human error.
Results showed that wound healing was impaired in people with diabetes, with a significant reduction in the numbers of fibroblasts found in the deep components of the wounds. This result must be treated with caution, as large numbers of multiple comparisons were used, potentially increasing statistical errors. However, these findings are not surprising as the sample population was at the extreme of the wound-healing spectrum and awaiting limb amputation.
The study failed to reflect reality, in that the wounds made were acute, small and identical. However, this method was deliberate, and to some degree advantageous, ensuring ease of comparison between wounds. An inability to compare wounds in other studies, because of large degrees of variance between wounds, has resulted in criticism of the methodology.
A better study design might have been to make larger wounds on individuals with diabetes who were not scheduled for amputation, and to compare these with similar wounds on a control population. However, this would have resulted in potentially greater risks for the subjects involved, making it difficult, if not impossible, to obtain ethical approval and recruit subjects.
Healing rates of diabetic wounds
Pecoraro et al (1991) used human subjects in a prospective study of 46 full-thickness, lower extremity, diabetic wounds that received wound care under a standard protocol.
The study examined early healing rates and final healing status. It concluded that variables such as age, diabetes type, duration of treatment, level or change in glycosylated haemoglobin, current smoking, presence of sensory neuropathy, ulcer location or class, and initial infection or frequency of recurrent infections were not significantly associated with initial ulcer healing and eventual status of tissue repair.
Initial healing rates were significantly associated with measurements of transcutaneous oxygen tension ([TcPO.sub.2]) and transcutaneous carbon dioxide tension ([TcPCO.sub.2]) around the wound. Statistically significant relationships were also found between eventual ulcer re-epithelialisation and Doppler arterial blood pressures at the dorsalis pedis, [TcPO.sub.2] and [TcPCO.sub.2]. These results support those of others regarding the predictive ability of [TcPCO.sub.2] for healing (Apelqvist et al, 1989).
[TcPO.sub.2] and [TcPCO.sub.2] were not found to be related to lower limb blood pressure values. The authors suggest that local factors in addition to arterial supply have a bearing on cutaneous oxygenation. Such factors may include aspects of capillary flow, diffusion from capillaries to tissues, or increased demands of tissue metabolism in the healing wound.
Study pitfalls: Although the overall study design is good and thorough, these results must be greeted with caution, as numbers in the study were small. The researchers themselves highlight this point by indicating that the beta factor should not be ruled out, i.e. statistical significance may have been demonstrated if the sample size had been larger.
The presence of oedema is cited as one of the factors that can affect the perfusion of oxygen to tissues (Pecoraro, 1991). Unfortunately, this study failed to consider oedema as an independent variable, and thus no attempt was made to quantify the oedema and relate it to healing and healing rates. The authors did mention that some of the subjects were given diuretics to help deal with the oedema; however, the protocol for doing this and the subjects who received the diuretics were not discussed. Such factors may have an important bearing on the final results.
In this study, patient compliance was not considered as a variable factor and was not examined. However, it is relevant to this study, as the subjects or their carers were requested to change the wound dressings once or twice a day, depending on the degree of exudate present. Failure to adhere to this aspect of the research protocol may have had a bearing on the final results.
Patient compliance should always be considered, particularly regarding wounds that are not healing within an expected timeframe. In practice, this may alert the podiatrist to a non-compliant patient. When examined further, the podiatrist may find that the patient is not wearing the recommended footwear that has been prescribed, is not resting as advised, or indeed is tampering with the wound. Such issues should be treated sensitively so as not to alienate patients and further reduce their compliance.
In light of this research, podiatrists must be cautious and not fail to examine all variables. They must ensure that negative factors are eliminated in an attempt to achieve adequate and timely healing. A need exists to repeat this research with larger numbers and to include those variables that have been omitted in the original work.
Wound healing at the cellular level
It has been hypothesised that if disturbances occur in diabetic wound healing, they do so in the inflammatory and proliferation phases (Loots et al, 1999). During the proliferation phases, the extracellular matrix is remodelled and rebuilt. Fibroblasts are the main producers of this extracellular matrix.
A study by Loots et al (1999) appears to be the first to examine the proliferation of fibroblasts from diabetic ulcers. Previous research has only involved non-lesion fibroblasts from people with diabetes (Vracko and Benditt, 1975; Rowe et al, 1977; Goldstein and Moerman, 1978, 1979).
Loots et al (1999) demonstrated that fibroblasts from patients with type 2 diabetes showed a significantly lower proliferation rate and an altered morphology in vitro compared with non-lesional and age-matched control fibroblasts from patients without diabetes. The researchers conclude that the diabetic process and the ulcer environment itself cause the fibroblasts to age. The overall functional activity of the fibroblast is thus reduced.
The study is beneficial in that it was the first of its kind. However, only four diabetic wounds were studied, and all occurred in patients with type 2 diabetes. The wounds were varied in location and duration, making accurate comparisons difficult. Neither wound sizes nor their aetiology were disclosed — factors that it is important to include. Future research would need to consider larger numbers of subjects, more uniform ulcerations with similar aetiologies, and a comparison with wounds found in people with type I diabetes.
A more recent study, involving non-lesional fibroblasts, showed that diabetic fibroblasts have a decreased proliferation response to growth factors, caused by a deficiency in growth factor receptor expression, compared with non-diabetic fibroblasts from sibling controls (Reenstra et al, 2001).
Role of fibroblasts
Fibroblasts have two main functions:
* The production of components of the extracellular matrix
* Wound contraction.
Consequently, a reduction in the number of fibroblasts will have a negative effect on these important aspects of wound healing.
On entering the wound space, fibroblasts become involved in the formation of granulation tissue. Within the wound, fibroblasts produce collagen (Martens et al, 1992), which is the most abundant protein within the extracellular matrix and contributes to the tensile strength of wounds.
Altered collagen metabolism
Research has shown that the defects that occur in diabetic wound healing may be caused by altered collagen metabolism and abnormal granulation tissue formation (Nagy et al, 1961; Madden and Peacock, 1971; Vogel, 1974; Hamlin et al, 1975; Oxlund and Andreassen, 1980; Goodson and Hunt, 1976; Monnier et al, 1984; Goodson and Hunt, 1986; Yue et al, 1986; Yue et al, 1987; Spanheimer, 1988; Spanheimer et al, 1988).
However, all these studies were carried out on diabetic rodents, which tend to be sick, malnourished and suffer from weight loss. These factors, in combination with hyperglycaemia, make it difficult to determine which variable is responsible for the granulation and collagen abnormalities (Pearch et al, 1960; Irvin and Hunt, 1974).
In an attempt to address this difficulty, Yue et al (1986) studied a small number of male Wister rats rendered diabetic by an injection of streptozocin at the recommended diabetogenic dose (Bell and Hye, 1983). Care was taken to ensure that the drug itself had no effect on the experimental results. This method of inducing diabetes is believed to have advantages over other methods, e.g. a lower mortality rate and resulting metabolic conditions that are more likely to resemble those of humans (Mansford and Opie, 1968).
Results showed that while animals with diabetes, uraemia and malnutrition all formed less granulation tissue, only in rats with diabetes was the level of collagen reduced. Collagen levels were, however, corrected with insulin therapy, reinforcing the need for good glycaemic control for adequate wound healing.
Study pitfalls: Care must be taken when interpreting these results because, unlike humans, rats can produce ascorbic acid, an important co-factor necessary for the production of collagen (Cohen and Mast, 1990). Thus results in such animals might not be the same as would be found in humans. Other pitfalls include potential human error when calculating the amount of collagen and granulation tissue present. The effect of the freezing process on excised cylinders must also be considered. Similar results were found in rats rendered diabetic by an injection of alloxan (Tengrup et al, 1988). However, the possible toxic effect of alloxan was not ruled out.
Research has been carried out to determine collagen accumulation in obese hyperglycaemic mice (Goodson and Hunt, 1986). This has the advantage that no chemicals are used to induce diabetes and thus there is no possibility of artificial methods interfering with research results.
Again, this research showed a decrease in the accumulation of collagen. But unlike Yue et al (1986), Goodson and Hunt (1986) failed to correct the collagen deficiency with insulin therapy. The researchers conclude that the adipose tissue in the obese animals might have hindered factors such as fibroblast activity, leading to a decrease in collagen production. This raises the question: do obese people with diabetes have altered healing compared with their non-obese counterparts?
Goodson and Hunt (1986) used Gore-Tex tubes to measure collagen accumulation (via hydroxyproline). These tubes are prone to extensive fibrous encapsulation, making it difficult to differentiate between connective tissue that has infiltrated the tube and that in the perimeter (Cohen and Mast, 1990). This potentially causes problems with the results. The effects of implanting foreign devices should be considered when analysing wound healing data, as these may potentially alter the healing response from that which would have occurred if wounding alone had taken place.
Collagen turnover has also been found to be reduced in diabetes (Spanheimer, 1988), and the degree to which this occurs is affected by the degree of hyperglycaemia (Spanheimer et al, 1988). These studies involved rats with diabetes that was induced with streptozocin. However, the dose used was significantly different from suggested diabetogenic doses (Bell and Hye, 1983), and the toxicity of streptozocin at this level was not determined, so the results may have been affected.
Application of research to wounds in people with diabetes
In general, research indicates that collagen levels are reduced in diabetic wounds (Yue et al, 1986; Spanheimer, 1988; Spanheimer et al, 1988). Thus if wounds do heal they will tend to have reduced tensile strength (Seifter et al, 1981; Andreassen and Oxlund, 1987). This is evident clinically, as people with healed diabetic ulcers are more prone to future tissue breakdown over previous ulcer sites.
This situation is further complicated by non-enzymatic glycosylation of collagen caused by hyperglycaemia (Pearl and Kanat, 1988; McInnes, 2001). This process results in the production of abnormal collagen, which is highly inflexible and prone to breakdown, particularly over pressure areas (Elkes and Wolfe, 1991).
People with diabetes are therefore prone to foot wounds, and once formed these are difficult to heal as a result of a combination of factors. The role of the podiatrist in the care of people with diabetes is thus essential.
Role of the podiatrist
Foot ulcerations and lower limb amputations are not an inevitable outcome of diabetes. This is highlighted in the St Vincent Declaration (World Health Organisation and International Diabetes Federation, 1990), which aimed to reduce the number of amputations in people with diabetes by 50% over a 5-year period. Twelve years on, this vision has still not been achieved and the provision of diabetic foot care within Britain is still variable (Mason, 1999a,b). The situation is not helped by a lack of good-quality research.
Lack of research
In a review of 2348 randomised, controlled trials regarding diabetic management, by the Cochrane Diabetes Group, only 3% were found to be related to the diabetic foot, with only four good randomised, controlled trials on the prevention of diabetic foot ulcers (Jude et al, 1999a). Practitioners must therefore become involved in clinical trials and researchers should ensure that sufficient numbers are recruited to the study, definitions of common terms are agreed, and wellreported methodologies are used. Local and regional standards need to be set and regularly evaluated. The podiatrist has a key role to play. The community and the hospital podiatrist must work closely together, and with other team members, to ensure the best outcome for their patients. Policies and procedures regarding rapid referral to hospital podiatrists for people with diabetes presenting with an at-risk foot must be in place.
The podiatrist has an important role to play in foot health screening of people with diabetes. This has been recognised in Northern Ireland by the Clinical Resource Efficiency Support Team (CREST, 1998), and throughout the UK by the Royal College of General Practitioners (Hutchinson et al, 2000) who advocate the need for an annual foot examination to detect patients at risk of diabetic foot complications.
Annual assessment should include vascular, neurological and footwear assessments, and inspection of the feet. Identification and removal of any callus formation at areas of pressure load by a skilled podiatrist is vital, as callus formation has been shown to be highly predictive of subsequent foot ulceration (Murray et al, 1996).
A retrospective survey of a diabetic population demonstrated the cost to individuals and the health service of not introducing annual screening (Deerochanawong et al, 1992). The study found that 47% of patients who had undergone an amputation had not had complete foot evaluations carried out in the year preceding initial ulceration or gangrene.
There is a need to educate staff involved in the care of people with diabetes to ensure that adequate measures are in place to help prevent diabetic foot disease (Macfarlane and Jeffcoate, 1997; Jude et al, 1999b).
Education is also important for the highrisk diabetic patient. Although evidence is inconclusive as to the best method of providing this education, it is thought that intensive education requiring action from both the clinician and the patient may reduce foot complications (Mason et al, 1999 a,b).
The podiatrist must not work in isolation, but as a member of a team. Research has shown that multidisciplinary teamwork can play an important part in reducing the incidence of major amputations in people with diabetes (Larsson et al, 1995). Key members of the team include the podiatrist, diabetes specialist nurse, diabetologist, vascular surgeon and orthotist (Boulton, 1998). Efforts should be made locally to ensure that all key personnel are involved.
Intervention to prevent amputation
If ulcers do result, they are susceptible to infection, which tends to be polymicrobial, to spread rapidly and to lead to overwhelming tissue damage (Edmonds et al, 1986).
At this point rapid intervention is necessary, and the podiatrist must treat and coordinate the action necessary to aid limb salvage, which includes the following:
* Control of infection
* Provision of pressure relief
* Onward referral if necessary. Others factors must also be considered, e.g.:
* Optimising glycaemic control
* Ensuring that diet is appropriate
* Encouraging smoking cessation
* Assessing oedema
* Encouraging patient compliance.
Despite the best efforts of the podiatrist and the team, a frustrating aspect of clinical practice is that a substantial number of ulcers fail to heal.
Wound healing products and the future
In an attempt to address such problems, products have been developed that not only help to maintain an ideal wound healing environment, but also add wound healing components to the environment. Such products include Dermagraft, Hyalofill, Promogran and Regranex. In terms of diabetic wound healing, this is a significant development as these products can help to address some of the deficits present at the cellular level.
Regranex (becaplermin) is a topical product consisting of platelet-derived growth factor, which has been shown to be both chemotactic and mitogenic for fibroblasts in vitro (Seppa et al, 1982). Clinical results are encouraging, as are published trials (Steed and the Diabetic Ulcer Group, 1995; d’Hemecourt et al, 1998; Weiman, 1998; Weiman et al, 1998), and recent reports indicate that the use of Regranex in the UK may be cost-saving (Ghatnekar et al, 2001). However, neither Regranex nor any of the other new breed of wound products appear to be the panacea for diabetic foot wounds. There is thus a need for ongoing quality research in this important area of health care, with the ultimate goal being to develop products that are universally effective in healing diabetic ulcers, and which minimise the risk of recurrence.
The podiatrist, as the professional primarily involved in diabetic foot care, must attempt to lead the way.
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RELATED ARTICLE: ARTICLE POINTS
1. The ‘diabetic foot’ can be considered as the neuropathic, ischaemic and neuro-ischaemic foot, with the neuropathic type being the most common.
2. Diabetic foot problems can develop extremely quickly, with tissue breakdown occurring rapidly and often complicated by infection.
3. The normal course of diabetic wound healing is hindered by many factors, including specific metabolic deficiencies and impaired physiological responses.
4. The podiatrist has a key role to play in the management of diabetic foot wounds and in the prevention of lower limb amputation.
1. There is a dearth of evidence regarding many aspects of diabetic foot care, including prevention, treatment and wound healing.
2. Much of the research on diabetic wounds has involved animals.
3. Collagen deposition is a key feature in cutaneous repair in both rodents and humans, although rodents obviously do not accurately replicate the healing process that occurs in humans.
4. Research using human subjects is, however, fraught with difficulties, such as the difficulty in obtaining ethical approval and indeed volunteers with diabetes who would permit areas of their bodies to be wounded for research purposes.
1. The study concluded that variables such as age, diabetes type, duration of treatment, level or change in glycosylated haemoglobin, current smoking, presence of sensory neuropathy, ulcer location or class, and initial infection or frequency of recurrent infections were not significantly associated with initial ulcer healing and eventual status of tissue repair.
2. Patient compliance should always be considered, particularly regarding wounds that are not healing within an expected time frame. In practice, this may alert the podiatrist to a non-compliant patient.
3. In light of this research, podiatrists must be cautious and not fail to examine all variables.
1. Fibroblasts have two main functions: production of components of the extracellular matrix and wound contraction.
2. If the number of fibroblasts is reduced, these important aspects of wound healing will be negatively affected.
3. On entering the wound space, fibroblasts become involved in the formation of granulation tissue. Within the wound, fibroblasts produce collagen, which is the most abundant protein within the extracellular matrix and contributes to the tensile strength of wounds.
4. Research has shown that the defects that occur in diabetic wound healing may be caused by altered collagen metabolism and abnormal granulation tissue formation.
1. The effects of implanting foreign devices should be considered when analysing wound healing data, as these may potentially alter the healing response from that which would have occurred if wounding alone had taken place.
2. In general, research indicates that collagen levels are reduced in diabetic wounds.
3. This is evident clinically, as people with healed diabetic ulcers are more prone to future tissue breakdown over previous ulcer sites.
4. Foot ulcerations and lower limb amputations are not an inevitable outcome of diabetes.
1. The podiatrist has an important role to play in foot health screening of people with diabetes.
2. Annual assessment should include vascular, neurological and footwear assessment, and inspection of the feet.
3. There is a need to educate staff involved in the care of people with diabetes to ensure that adequate measures are in place to help prevent diabetic foot disease.
4. Research has shown that multidisciplinary teamwork can play an important part in reducing the incidence of major amputations in people with diabetes.
Janet Close-Tweedie is Chief Podiatrist, Antrim Area Hospital, Northern Ireland.
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