Healing Chronic Infected Foot Wounds
with Human Fibroblast-Derived Dermal
Substitute and Silver Dressings

D iabetic lower-extremity ulcers are associated with significant morbidity and mortality. Although recent outcomes in the treatment of diabetic lower-extremity ulcers seem to trend toward improved, there has been only little dramatic change in overall treatment and results.^1–3 It is estimated that more than 600,000 amputations are performed annually in patients with diabetes in the United States.^3,4 It is further estimated that approximately half of these patients will develop ulceration and infection in the contralateral limb in the 18 months following amputation.^3,4 Slightly more than half of these patients, in turn, have contralateral amputations in 3 to 5 years, and their mortality rate after the first amputation is 20–50%.^3,4 Individuals with diabetes also have an increased risk of infection with subsequent complications secondary to impaired macrophage and cellular immune responses.^4–7 Their nonhealing lower-extremity ulcers may lead to lower-extremity amputation, which is at least 14 times more likely to occur in persons with diabetes than those without diabetes.^3,4 In 1997, inpatient, outpatient, and outpatient pharmaceutical medical expenditures incurred by the diabetic population totaled $77.7 billion.^3,4 The total direct and indirect cost of care related to diabetes was estimated at $98 billion.^3,5 Recent articles^4,6 reported costs for nonoperable treatment of a single ulcer to be $7,000–$8,000. Treatment of infected ulcers cost more than $17,000, while amputations cost almost $45,000. Lower-extremity wounds associated with arterial insufficiency have poor healing potential. For this reason, they are typically excluded from clinical trials for wound healing treatments. As a result, many wound healing products are contraindicated in ischemic wounds. However, arterial insufficiency is a frequent complicating factor in many lower-extremity wounds, including nonhealing leg and foot ulcers in patients with diabetes.^1,3,7,8 In the United States, the incidence of amputations for ischemic disease was estimated to be 2.5 per 10,000 per year.⁵ Although revascularization is accepted as the primary means of reducing the risk of amputation in these patients,^6,7 some patients are not able to receive revascularization due to medical comorbidity or the lack of a suitable outflow vessel in the limb. Nehler et al.⁸ suggested primary amputation for such patients. In addition, some patients may receive revascularization and do not achieve results that completely alleviate ischemia due to diminished number of outflow vessels, focal ischemia due to smaller vessel blockage, or lack of collateral arterial flow.^9,10 In the authors’ wound healing practice, a large number of patients with diabetes who are maximally treated for ischemia are seen with recalcitrant, nonhealing, lower-extremity wounds. Some degree of ischemia is apparent in the majority of these patients. The authors have developed a variety of techniques for dealing with these wounds, including medication and advanced wound healing techniques.¹⁰ These techniques are reported here.^11–16 Materials and Methods Thirty consecutive patients with diabetes, ischemia, and chronic wounds of the ankle and foot were treated over an 18-month period. Patients had appropriate moist wound care, and their wounds failed to heal for 5 weeks or more (average = 11 weeks, range 5–60 weeks). All patients were ambulatory and had a history of at least 1 severe infection of the wound area (average 1.5, range 1–3). Wounds were colonized with methicillin-resistant Staphylococcus aureus (MRSA) (12), vancomycin-resistant enterococcus (VRE) (5), or MRSA and another organism (13), usually pseudomonas or a streptococcus species. All cultures from the episodes of cellulitis were positive for VRE, MRSA, or both, and these were the suspected infecting organisms. All patients gave informed consent for their procedures. All cases were initially referred to and seen weekly by the same physician (SNC). The patients in this report received most of their wound care on an outpatient basis. Wound size varied from 2.0 cm x 3.2 cm x 0.3 cm to 8 cm x 5 cm x 1 cm (average = 22.5 cm³). All patients had modest-moderate neuropathy as determined by the physician on initial examination with use of a disposable Semmes-Weinstein monofilament. Ages were 22–83 years (average 62 years). There were 14 men and 16 women. Five patients were in renal dialysis. Pain was assessed throughout the treatments using a 0–10 visual analog pain scale where 0 is no pain at all and 10 is the worst pain imaginable.¹⁷ All wounds were offloaded as needed prior to wound treatments. Diabetic and nutritional status was assessed and corrected when needed, but a strict control of diabetes was not achieved (average HbA1c was 7.5, plasma glucose 160–200 mg/dL). All patients had some form of arterial ischemia as determined by arterial duplex Doppler scans, toe pressures of 35–50 mmHg, and ankle brachial indices. Ischemia was corrected as much as possible in all patients. Twenty patients received bypass or angioplasty for their lower-extremity ischemia. Ankle brachial index (ABI) was defined as the ratio of the systolic blood pressure in the ankle divided by the systolic blood pressure at the arm. The tools required to perform the ABI measurement included a hand-held 5–10 MHz Parks Model 811-B Doppler probe (Parks Medical Electronics, Inc., Aloha, Ore) and a blood pressure cuff. The ABI was measured by placing the patient in a supine position for 5 minutes. Systolic blood pressure was measured in both arms, and the higher value was used as the denominator of the ABI. Systolic blood pressure was then measured in the dorsalis pedis and posterior tibial arteries by placing the cuff just above the ankle. The higher value was the numerator of the ABI in each limb. The diagnostic criteria for peripheral arterial disease (PAD) were based on the ABI and interpreted as follows: normal 0.91–1.30; mild obstruction 0.70–0.90; moderate obstruction 0.40–0.69; severe obstruction 1.30. A modified Parks Model Pneumoplethysmograph was used to measure toe pressures. After the patient was admitted to the wound care program and offloaded where needed, correction of nutrition and diabetes control was reasonably obtained. It is noteworthy that at least half of the patients seen still required offloading of the chronic wounds. Moist wound care dressings with hydrogel and maintenance sharp debridement were continued until successful offloading was achieved. Since no progression of healing had been noted, patients were treated with human fibroblast-derived dermal substitute (Dermagraft™, Smith & Nephew Inc., Largo, Fla) and silver dressings (Silverlon™, Argentum Medical LLC, Willowbrook, Ill). Sharp debridement of the wounds was performed prior to application of the dermal substitute and silver dressing and was repeated as necessary throughout the course of therapy. The dermal substitute was thawed and applied to the wound area. The silver dressing was moistened with water and placed over the dermal substitute. The silver dressing was changed every 7 days. A dressing consisting of a hydrogel and semi-occlusive gauze was placed over the silver dressing to provide moisture as needed. The dermal substitute was not debrided, and a new dermal substitute was applied over the previous graft at 15-day intervals. Wounds were debrided at this dressing change if necrosis and excessive slough were present. Care was taken not to disturb the grafts, although most graft tissues were incorporated at this 15-day interval. The healing progression of the wounds was evaluated weekly. If no response to the dermal substitute was noted after 2 grafts, no additional dermal substitute would be offered; however, this did not occur. When wounds were thoroughly granulated, and if no clinical infection was present as determined by clinical signs and symptoms (ie, erythema or excessive swelling in the wound area, significantly increased pain in the area, purulent discharge collected beneath the skin or draining from the wound, foul odor from the wound, systemic signs of infection), the patient would continue on moist wound care using silver dressings without a dermal substitute.18 If epithelization did not begin and progress over the next 2 weeks, a skin graft would be offered. Results Seventeen patients progressed to satisfactory healing and spontaneous closure by 84 days (average 46 days, range 32 to 94 days). Eight patients required skin grafts that healed. All patients had ABIs recorded, and none of the patients were categorized into the incompressible group. Previous studies suggested that results of toe pressure measurement are predictive of wound healing.⁹ These studies reported that wounds with toe pressures 10 Table 1 lists the patient population characteristics, including ABIs. Five patients did not heal and required amputation. Two patients required single toe amputations and had toe pressures Staphylococcus aureus, vancomycin-resistant enterococcus, or both. Clearly, not all wounds were infected at all times, but cultures were consistent throughout this report. Patients were regularly treated in the wound care program with maintenance sharp debridement and moist silver dressings. A dermal substitute was applied with silver dressings every 15 days until healing or skin graft application. Seventeen patients progressed to satisfactory healing and spontaneous closure (Figure 1–3). Eight patients required skin grafts that subsequently healed. Healing was maintained on follow-up at 8 weeks in all patients. There were no episodes of cellulitis or infection once silver dressings were instituted. Five patients required amputation for their nonhealing wounds, and all of these wounds subsequently healed. The patients with nonhealing wounds who required amputation were those patients with greater ischemia as compared to the group as a whole, but other patients had similar ischemia and healed. In the amputation group, 3 patients were on dialysis, while only 2 patients who healed were on renal dialysis. Pain was markedly relieved once healing had begun with use of silver dressings and the dermal substitute but was also relieved in those patients that underwent amputation after institution of silver dressings and the dermal substitute. Chronic foot and lower-extremity wounds of patients with diabetes generally occur as a result of unrecognized neuropathy and repetitive trauma that results in injury. Once established, these wounds in patients with diabetes may not heal and may lead to limb loss. Despite the progress that has been made in recent years to better understand and treat these complex chronic wounds, many wounds still do not respond well to existing treatments.^19,20 These wounds frequently have other contributing factors including arterial ischemia and infection.²¹ All of these complicating factors were present in the wounds seen here, which required multimodal advanced wound care including dermal substitutes and silver dressings. It is likely that multiple components of the dermal substitute (ie, growth factors, cytokines, matrix proteins, and glycosaminoglycans) that are not found in the other modalities assisted in this process of wound repair and provided a substrate that allowed fibroblast and epithelial cell migration that eventually achieved wound closure.²² Clinically, patients are developing more frequent infections and colonization with antibiotic-resistant bacteria.^23,24 Concomitantly, new roles for broad-spectrum antimicrobial dressings are being continuously found.²⁵ Silver dressings have no apparent sensitizing effect that frequently accompanies topical antibiotics and chemicals, and silver at concentrations readily found in the silver-plated cloth dressings do not appear to induce resistance.²⁶ Additionally, use of silver dressings may have other effects potentiating healing, including epithelization.²⁷ The antimicrobial effect as well as the increased healing potential and epithelization has prompted the authors to use these dressings to cover skin grafts placed over chronic wounds and as a primary dressing for chronic wounds. Reduction of pain and concomitant inflammation, slough, and odor has been reported with silver dressings as seen here.²⁷ As noted, this is a highly desirable effect that is particularly useful in the trauma and wound patient who has chronic, severe pain. Conclusion Many treatments have been developed and are utilized to treat ischemic wounds. The authors’ approach to treatment, like many, is a combination of multiple advanced wound healing modalities and techniques. It is clear that any initial physical arterial obstruction should be corrected as best as possible before continuing treatment. In many instances, this will not result in total circulatory correction as reported here. The use of dermal grafts and silver dressings can be useful in obtaining full wound healing and assisting in wound closure.