A prospective, randomized, twenty-four center study of 208 patients was conducted to determine the safety and efficacy of Apligraf in comparison to conservative treatment, saline moistened gauze, in the treatment of diabetic foot ulcers. One hundred and twelve patients received Apligraf and 96 received control. Complete wound closure was evaluated by 12 weeks. In a Kaplan-Meier life table analysis, median times of 65 and 90 days were shown for the Apligraf and control patients respectively (p = 0.0026). A Cox's Proportional Hazards Regression Analysis of these data determined that Apligraf increased the probability of complete wound closure by 59% (Risk Ratio = 1.59, p = 0.0001). The overall incidence of complete wound closure was 56.3% (63/112) for Apligraf and 37.5% (36/96) for control patients (p = 0.0042). At six months, the incidence of ulcer recurrence was 5.9% in the Apligraf group and 12.9% in the control group. The rate of adverse reactions was comparable between the two groups except for the incidence of osteomyelitis (2.7% Apligraf vs. 10.4% control, p<.05) and amputations (15.6% Apligraf vs. 6.3% control, p<.05). We conclude that Apligraf may help in reducing the spread of infection to deep structures, such as bones and tendons by healing more diabetic foot ulcers in a shorter period when compared to conservative treatments.

Introduction
Diabetic foot ulceration (DFU) is a major problem that significantly impairs the quality of life of the patient, leads to prolonged hospitalization and may eventuate in a major amputation. Foot problems affect 15% to 20% of all persons with diabetes and are the reason for 20% of all diabetes-related hospital admissions and more than 50,000 lower extremity amputations per year in the United States (1,2). The cost of DFU is also significant; the attributable cost for a middle-aged diabetic man with a new foot ulcer has been recently estimated to be $27,987 for the first two years after diagnosis (3).

Apligraf® (Graftskin) is a living, bi-layered, skin substitute which contains Type I bovine collagen, extracted and purified from bovine tendons and viable allogeneic human fibroblast and keratinocyte cells isolated from human infant foreskin. Apligraf consists of two primary layers. The upper 'epidermal-like' layer, formed of living human keratinocytes, has a well differentiated stratum corneum which has been shown in in vitro experiments to provide a natural barrier to topical infection and wound desiccation. In the supporting 'dermis-like' layer of Apli-graf, the major cell type is the fibroblast. Apligraf fibro-blasts produce many of the matrix proteins found in human dermis, such as collagen type IV, tenascin, decorin, hyaluronate, and fibronectin. In addition, collagen type IV, laminin, laminin 5, heparin sulfate, proteoglycan, and ß4 integrin are present at the dermal epidermal junction. Apligraf also expresses many of the cytokines found in human skin including PDGF-A, PDGF-B, TGFa, TGFb1, TGFb3, ECGF, FGF-1, FGF-2, FGF-7, IGF-1, IGF-2, CSF, IL-la, IL-6, IL-8 and IL-1l. Other cells found in human skin, Langerhans cells, melanocytes, macrophages and lym-phocytes as well as secondary structures such as blood vessels and hair follicles are not present in Apligraf. Apligraf has demonstrated the property of healing itself when perforated or meshed.

In the present study we have evaluated the safety and efficacy of Apligraf in the management of chronic diabetic foot ulcers in a multi-center, randomized controlled trial.