INTRODUCTION
Wound healing is a highly complex and tightly organized regenerative biological and cellular response to tissue injury. In healthy patients, wounds normally heal in a timely and orderly fashion initiated through a process of cell replication and migration, protein synthesis, and matrix deposition, and, finally, tissue organization and maturation that restores cellular activity, tissue integrity, and barrier function. Although interesting from an academic standpoint, this distinction may be artificial because the course of cutaneous wound healing is more like a cascade of interdependent events.
Foot ulcerations develop in approximately 15% to 20% of individuals with diabetes.1-3 The goal of wound management is to achieve accelerated closure with complete healing, potentially reducing hospitalizations and mortality and morbidity linked to amputation, as well as the economic burden associated with diabetic foot ulcerations. Approximately 85% of lower extremity amputations occurred in patients who presented with diabetic foot ulcerations as an antecedent to surgical amputation.4 The 5-year mortality rate in diabetic-induced limb amputations was reported at 39% to 68%.5 Major risk factors for the development of diabetic foot ulcers include peripheral neuropathy, peripheral vascular disease, and high or abnormal foot pressures. Diabetic peripheral neuropathy has several effects on the lower extremity. First, autonomic dysfunction and associated denervation of dermal structures cause decreased sweating, drying of the tissues, and thus loss of integrity of intact skin, providing an ideal site for microbial invasion. Somatic neuropathy results in sensory loss in the affected area, making it difficult for patients to notice or to feel an ulcer. In such cases, the patient may not seek treatment until after the wound progresses and becomes infected.6
The cost associated with the management of diabetic foot ulcers, hospitalization, and amputation is enormous. Excluding the cost of amputations, the 1986 statistics for treating patients with type 2 diabetes for chronic skin ulcerations was $150 million in the United States alone.7 The estimated cost of treating 1 diabetic foot ulcer for a 2-year period is estimated at $28,000.00.8 Of the patients who required lower extremity amputation, the associated cost per episode in the United States ranged from $20,000.00 to $60,000.00.9
Redekop et al,10 using a Markov model analysis of Apligraf (Organogenesis Inc, Canton, MA), demonstrated a 12% reduction of costs for the first treatment compared with standard wound care alone. This study suggests that the reduced time to heal coupled with a reduced risk of amputation to a large extent offset the initial cost of Apligraf.10 The efficacy of Apligraf in the treatment of chronic wounds has been demonstrated in several large randomized controlled trials. In diabetic foot ulcers, Veves et al11 reported a significant improved healing rate of 56% versus 38% (P = .0026) and a reduced time to heal of 65 versus 90 days in patients treated with Apligraf with standard wound care compared with patients treated with standard wound care alone. The Apligraf-treated group experienced a significantly lower incidence of osteomyelitis and amputation than the control group (P < .05).11
METHODS
Apligraf is a living bilayered cell therapy and supplied in applications measuring 7.5 cm in diameter. The product does not need to be stored in any special container or freezer. Apligraf has a 10-day shelf life and undergoes extensive safety screening and is subject to rigorous quality control measures. The product has been used in more than 120,000 patient applications.10,11
In this case study, informed patient consent was obtained before the procedure. Apligraf was applied to the ulceration under clean technique after debridement or wound excision of the ulcer. For the patients who received more than 1 application, the minimum time between reapplication was 4 weeks. Ulcerations were located on the plantar, posterior, medial, or the lateral aspect of the heel. Pressure offloading was strictly adhered to throughout the study. Devices used to offload included a surgical shoe, wheelchair, walker, or a controlled ankle-motion walker. Vascular status was evaluated in all the patients and was deemed adequate to heal if the pedal, popliteal, and superficial femoral pulses were palpable. The palpable presence of pulses throughout the lower extremity was considered an adequate sign of the potential to heal. Noninvasive arterial vascular studies were performed on patients who did not meet this criterion.
Osteomyelitis was diagnosed in patients by the presence of obvious destruction on radiographs or magnetic resonance imaging evaluation, or both, and appropriate antibiotics were initiated. Patients with osteomyelitis were not excluded from the study, as it was believed they had the potential to heal adequately when the presence of osteomyelitis was identified and treated. Treatment, as deemed appropriate by the author, consisted of either antibiotic management, surgical excision, or both.
RESULTS
To review the benefits of Apligraf in the treatment of heel ulcers, 10 ulcers from 9 patients were evaluated. Of the 10 ulcers, 4 were in women (patients 2, 5, 6, and 7), and 6 were in men (patients 1, 3, 4, 8, 9, and 10). Eighty percent of the patients had a history of diabetes (patients 1, 2, 3, 5, 7, 8, 9, and 10). The remaining 20% of the ulcers were associated with venous disease (patients 4 and 6). Two of the patients were smokers (patients 1 and 2). Regarding the location of heel ulcers, 5 were located on the plantar aspect (patients 2, 3, 8, 9, and 10), 4 were located at the posterior aspect of the heel (patients 1, 5, 6, and 7), and 1 was on the medial aspect of the heel (patient 4). Seven of the ulcers were to subcutaneous tissue (patients 1, 2, 4, 7, 8, 9, and 10), one was at the level of the Achilles tendon 3 cm proximal to its insertion to the heel (patient 5), and 2 were to the calcaneal bone (patients 3 and 6). Two of the patients had osteomyelitis at the calcaneus (patients 3 and 6). Two of the patients had impaired arterial circulation with both having an ankle-brachial index of 0.6 (patients 1 and 3). The remaining patients were considered to have adequate arterial circulation by the presence of palpable pedal, popliteal, and superficial femoral artery pulses. The average size of the ulcer before initial debridement was 5.88 cm2. The average age of the patients was 57.5 years.
The patients in this study had ulcers for an average 161.3 days before the initiation of Apligraf. The average time to complete healing for all the patients was 44 days. The average time that the ulcer was present before the graft application in patients who used tobacco was 175.4 days, without tobacco was 175.4 days. The average time to complete healing of the ulcer in patients who used tobacco was 60.5 days, without tobacco was 39.9 days. The average time that the ulcer was present before the graft application in patients who had osteomyelitis was 162 days, without osteomyelitis was 161.0 days. The average time to complete healing of the ulcer in patients who had osteomyelitis was 44 days, without osteomyelitis was 49.5 days. The results are summarized in Table 1.
CASE REVIEW OF SELECTED PATIENTS
Case 1
Patient 2, a 39-year-old woman with diabetes and a 15-year history of smoking presented with a benign soft-tissue mass at the plantar aspect of the heel. The mass was surgically excised with complete incision dehiscence (Figure 1A). Initial wound care of a topical antibiotic and dry sterile dressing changes were carried out for 35 days without improvement. Site preparation that consisted of wound bed preparation by surgical excision, followed with the initial application of Apligraf, was undertaken with a significant reduction in ulcer size (Figures 1B and C). A second application was performed with complete ulcer healing at 80 days (Figures 1D and E). There was no recurrence at the 2-year follow-up.
Case 2
Patient 7, a 78-year-old woman with diabetes, presented with posterior heel ulceration down to the level of subcutaneous tissue (Figures 2A and B). This ulceration was open for 406 days. The ulcer was excised, and Apligraf was applied (Figure 2C). Complete healing occurred in 35 days. There was no recurrence at the 1-year follow-up (Figure 2D).
DISCUSSION
Although the sample size of the patients evaluated for the benefit of bilayered cell therapy in treating heel ulcerations was not large enough to draw statistically significant conclusions, several important clinically related benefits were identified. Apligraf was beneficial in treating heel ulcerations in patients with a history of diabetes, as well as those patients with underlying venous disease. In patients with heel ulcers that were open for an average of 161 days or 23 weeks, accelerated healing occurred at an average of 44 days or 6 weeks. Accelerated healing was also found in patients who smoked, with healing at 60.5 days or 8.5 weeks. The nonsmokers achieved complete healing at 6 weeks. This suggests that, although there is some delay in healing associated with tobacco use, Apligraf was beneficial in healing heel ulcers in smokers as well. Smoking cessation education and resources, however, should be offered to all patients seen in wound care practices. Little difference was evidenced in the time to heal between the patients with osteomyelitis and those without osteomyelitis. This would suggest that living bilayered cell therapy may be beneficial in patients who have an ulcer and have the diagnosis of osteomyelitis.
Additional studies with larger enrollment would verify these initial findings.
CONCLUSION
Data suggest that ulcers of long duration do not respond to conventional therapy and require adjunctive interventions. In addition, it is now possible to predict which wounds will not heal after 3 to 4 weeks of conventional therapy, thereby clarifying when advanced therapies are indicated to reduce morbidity and overall cost of care for chronic wounds. The primary goal of treatment for chronic wounds is to restore both a functional and aesthetically pleasing tissue barrier.
Conventional treatment for established wounds incorporates common principles that apply to the management of all wounds, including debridement of necrotic tissue, maintenance of a moist wound bed, and control of infection. Although most products augment the healing process by overcoming certain conditions and deficiencies in a nonhealing wound, few products provide the necessary range and requisite ratios of essential cellular and extracellular materials necessary to act as a true cellular replacement system.
This study suggests 3 possible benefits from heel ulcer management with living bilayered cell therapy. First, Apligraf may accelerate healing of heel ulcerations in patients with diabetes and patients without diabetes who have venous disease. Second, although smoking can delay healing in ulcers, living bilayered cell therapy may accelerate healing in these types of ulcerations. Third, based on previously reported data from randomized controlled trials,10,11 living bilayered cell therapy may be used to reduce the incidence and progression of an ulcer with underlying osteomyelitis. Living bilayered cellular therapy provides healthy replacement cells of dermal and epidermal origin, as well as the growth factors, cytokines, and proteins. When used in conjunction with the principles of evidence-based wound care, Apligraf may facilitate a reduction in overall patient morbidity and mortality with a consequent reduction in health care utilization and restoration of function.
REFERENCES