Regional Burn Center Wound Clinic, University of California San Diego Medical Center, California, USA
Introduction
The association of diabetic foot ulcers with a high incidence of amputation, morbidity and mortality is well documented in the international literature including guidelines from the American Diabetes Association, the International Consensus Panel of Diabetic Ulcers, and the German literature on Diabetic Foot Syndrome [13]. The cost of care incurred by the diabetic with foot lesions is surpassed only by the total cost of medical problems related to the disease. A brief review of the pathophysiology of diabetic ulcers and an understanding of the difference between chronic wounds will facilitate decisions related to the use of new technologies, including recombinant growth factors. The following overview of new technology related to diabetic foot ulcer care will summarize relevant information related to acute versus chronic wounds, assist in defining a chronic wound, and provide concise guidelines on appropriate prescription of new technologies.
Acute vs chronic wound healing
The cellular mechanism of wound repair in the acute wound has been extensively studied and documented in the medical literature [46]. The inflammatory, proliferative (granulation phase) and remodelling phases can be categorized according to the activity of their cellular components, including cytokines, chemical mediators, and cellular components [7]. Intrinsic medical conditions or extrinsic environmental factors rarely affect the repair process in the healthy individual.
The chronic wound, in contrast to the above, has phases of repair that do not follow the expected sequence of healing. Wound treatment experts in the United States have made attempts to define chronic wounds [8].
Unresponsive wounds on debilitated patients and those with multiple medical problems must be addressed based on a triad of care. Intrinsic, extrinsic and wound environment factors must be simultaneously treated for optimal outcomes. Intrinsic factors include the patient's medical status, prescribed medications and concomitant disease. Extrinsic factors concern repetitive trauma, off-loading and pressure reduction. The wound environment examination includes, but is not limited to, the wound bed status (amount of necrotic tissue, type and amount of exudate, fibrotic tissue, per cent granulation, re-epithelialization), cellular activity in the wound, and devices and dressings used for treatment. When applied to the diabetic, the above triad translates to control of the diabetic disease, selection of appropriate shoes and devices to reduce or eliminate pressure on the lower extremity, and aggressive wound debridement, treatment and dressing selection. Neglecting any one of the three approaches to the unresponsive wound may delay or prevent wound closure.
Definition of chronic wounds
The majority of wounds that are considered chronic respond to established treatment and dressing regimens. However, 1520% of patients with chronic wounds do not respond to conventional therapy and may require the use of advanced technologies to stimulate and expedite tissue repair. The physician needs to differentiate between a responding chronic wound, which will close with conventional treatment, and a truly non-responding wound, which will require a different approach.
Pecoraro et al. [9] determined that not all diabetic ulcers are responders. Those ulcers not showing a reduction in size in a one-month treatment period with good pressure reduction and ulcer therapy can be classified as non-responders. Furthermore, Sihl et al. [10] determined that approximately 15% of all diabetics under good control would still not demonstrate normal healing rates. The delay in wound repair may be attributable to endogenous wound factors including senescent cells, absence of growth factors, and other cellular abnormalities. Agren et al. [11] found that fibroblasts in diabetic ulcers, as with venous ulcers, are diseased. Wounds that remain open for extended periods of time are more likely to have diseased cells. Phillips et al. [12] described the presence of senescent cells at the margins of chronic venous ulcers. Senescent cells are characterized by cells, which are viable but have lost their proliferative capacity. The latter cells would not be expected to respond well to the presence of endogenous or exogenous growth factors in the wound milieu. Debridement of senescent cells, non-viable tissue, fibrotic tissue, wound debris, and other unwanted wound components may significantly expedite wound closure while increasing the availability of viable cells able to produce and respond to growth factors and other cytokines. Debridement and its correlation to the significant increase in wound closure, particularly when followed by the application of platelet-derived growth factor (rhPDGF-BB) is supported by a large randomized double-blinded and controlled trial [13].
The presence of a prolonged inflammatory response may further delay closure by promoting on-going activity of matrix-metaloproteinases [MMP). High levels of MMP activity may contribute to protein and growth factor degradation. Repetitive trauma and high levels of bacterial colonization may result in increased inflammation activity with an associated influx of macrophages and neutrophils. Appropriate levels of MMP activity during the phases of wound repair are known to promote wound repair, while prolonged levels may delay closure through matrix, growth factor, and growth factor receptor degradation [14].
Advanced technology for diabetic foot ulcers
The use of advanced technology, including platelet-derived growth factor, may assist with wound closure in the diabetic patient. Based on medical literature, the clinician should be able to determine within the first few weeks of treatment, whether a wound will respond to conventional therapies (responders) or remain chronic (non-responder).
Available literature suggests that a visible decrease in wound size during the first few weeks of administering appropriate wound care is an indicator of chronicity. Wounds that decrease in size by greater than 0.109 cm per week have been found to correlate with responsive wounds, while rates less than 0.032 cm per week are classified as non-responders [15]. A decrease in surface area of less than 10% per month may also correlate with non-responding chronic wounds. Once a physician has established the status of a wound as being chronic, advanced modalities may be selected to improve treatment and cost outcomes.
Diabetic ulcers, which remain open, are associated with increased cost of care and morbidity [1618]. Foot ulcers are known to significantly affect the cost of care in diabetic patients. Shortening the time to closure by even a week may prevent infection, complications and ulcerations. The cost of amputation well exceeds the cost of wound closure and limb salvage. The cost of growth factor therapy may be less than the cost of other prescribed medications and antibiotics used in the course of standard care when an ulcer remains chronic. Growth factors need to be considered for appropriate and advanced care of the non-responding diabetic foot lesions and chronic wounds.
Recombinant platelet derived growth factorrelevance to diabetic foot ulcers
The complications and cost associated with unresponsive diabetic foot ulcers has prompted extensive biomolecular research during the last decade. Chemical mediators, including growth factors, have received particular attention as a result of their importance in stimulating and directing cellular activity in the wound environment. While various growth factors have been studied, the only government approved prescription drug (approved in US, UK, Germany and Austria) is becaplermin (recombinant platelet-derived growth factor or rhPDGF-BB).
The wound environment contains a variety of growth factors. Platelet-derived growth factor is of particular relevance due to its chemotactic, mitogenic, angiogenic, and stimulatory effects leading to matrix formation and wound bed granulation [19,20]. PDGF may be of significant benefit of diabetics as recalcitrant diabetic wounds have been found to be deficient in or absent of PDGF [21]. A total of 922 patients have been studied in well-designed and controlled trials and have resulted in data supporting safety and statistically significant benefits [19,22]. A phase III randomized placebo-controlled double-blind study on 382 patients with diabetic foot ulcers supported that becaplermin gel 100 µg/g, in conjunction with good wound care, significantly increased the incidence of complete wound closure and significantly reduced the time to complete closure of chronic diabetic neuropathic ulcers [21].
Experience by the author with becaplermin during the last 2 years at the University of California San Diego Medical Center, Regional Burn Center Wound Clinic, has supported a significant cost and treatment benefit when used on patients with diabetic foot ulcers as well as ulcers of other aetiologies. Application has been extended beyond diabetics to wounds of other aetiologies. Figure 1 illustrates a patient with a large tissue effect exposing underlying tendons of the foot. Grafting is necessary to decrease the risk of limb loss but is made difficult by the full-thickness nature of the wound. Application of rhPDGF-BB once a day for a 2-week period resulted in rapid granulation (Figure 2
). The patient was successfully grafted and the trauma and expense of limb loss avoided. Growth factor therapy may be cost and treatment effective when applied to non-responsive wounds that have been appropriately prepared through removal of necrotic and fibrotic tissue.
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Aggressive and complete debridement of all wound debris, necrotic, fibrotic, and non-viable tissue from the wound bed is necessary for optimal therapy response. Steed et al. [13] studied the effects of debridement on response to rhPDGF-BB in randomized-blinded placebo-controlled studies. Results were consistent with improved tissue repair correlating with debridement. Debridement in conjunction with growth factor therapy resulted in a statistically significant difference between placebo and drug therapy. Receptors for growth factors may be found on viable cells and not necrotic tissue. Removal of the necrotic tissue increases the number of available receptors allowing interaction between cells and applied drug therapy.
Vascular exams are necessary to determine whether sharp debridement is appropriate. When sharp/surgical debridement is not possible, alternative means of wound cleansing, including enzymatic, mechanical, and biological can be considered [22].
Control of infection and high levels of contamination reduce the negative effect of prolonged inflammation and high levels of enzymatic activity on proteins including growth factors and growth factor receptors [14,23]. Debridement, unless contra-indicated, assists with the removal of necrotic tissue, lowers bacterial count, and may provide an environment optimal for tissue repair.
Summary
Advanced and developing biotechnologies, including growth factors, are offering new approaches to the treatment of difficult-to-treat wounds. The majority of chronic wounds (responders) may respond well to conventional therapies. A smaller, yet significant percentage of patients (1520%) may have recalcitrant (unresponsive) wounds that do not decrease in size with standard care. The latter population may experience rapid closure with the application of growth factors. While current indications are for diabetic neuropathic foot ulcers of specific size and duration, growth factors are not disease specific and may bind to receptors on wounds of any size and of non-diabetic aetiology. Clinicians may attempt the use of these cytokines for full-thickness and large wounds of non-diabetic etiologies. As growth factors may be deficient in patients with diabetes or other recalcitrant wounds, use of advanced modalities, including PDGF, need to be considered to expedite wound closure, reduce disease-associated morbidity, and to lower the cost of care. Physician and patient education on appropriate use and mechanism of action will further ensure optimal outcomes.
Notes
Correspondence and offprint requests to: G. D. Mulder, Regional Burn Center Wound Clinic, University of California San Diego Medical Center, 200 West Arbor Drive, San Diego, CA 92103-8896, USA.
References