Introduction

Patients with diabetes are at increased risk of developing foot ulcers. Peripheral neuropathy increases the likelihood of foot injury, and peripheral vascular disease reduces normal healing of minor trauma, allowing development of ulcers. It is estimated that 15 percent of patients with type 1 or type 2 diabetes will develop an ulcer on a foot or ankle within the course of the disease.[1,2] Current standard care for diabetic foot ulcers includes removal of mechanical stress, sharp wound debridement, and use of dressings to maintain a moist wound environment.[2] In addition, infections of the wound site must be managed. Rates of healing with standard care are 24 percent after 12 weeks.[3] A majority of patients with failure of wound healing ultimately require surgery or amputation, and ulcers contribute to 85 percent of lower-extremity amputations for patients with diabetes.[4,5] The development of a new foot ulcer by a 40- to 65-year-old man can generate nearly $28,000 in additional cost of care during the two years after diagnosis.[6]

The need to improve the success rate of healing in diabetic ulcers has prompted new therapeutic approaches. Biologic dressings, such as cultured epidermal allografts, can promote healing of a variety of wounds, including burns, venous ulcers, and split-thickness skin graft donor sites.[7–13] Because the allograft cells survive only briefly and do not become a permanent part of the regenerating tissue,[14] the postulated mechanism of action of cultured grafts is stimulation of wound repair through the release of multiple cytokines and matrix components.[15–18]

Bilayered cellular matrix (BCM, OrCel™, Ortec International, New York, New York) is a porous collagen sponge containing cocultured allogeneic keratinocytes and fibroblasts harvested from human neonatal foreskin. This device has been approved for use in the United States (US) by the Food and Drug Administration (FDA) for the treatment of split-thickness donor sites of burn patients and in patients with mitten-hand deformities secondary to recessive dystrophic epidermolysis bullosa (RDEB).[19] BCM is not approved by the FDA for use on diabetic foot ulcers. The objective of the current study was to examine the effectiveness and safety of treatment of diabetic neuropathic foot ulcers using BCM plus standard care compared with standard care alone.

Methods

Study population. Patients included in the study were of either sex, between 18 and 85 years old, and had either type 1 or type 2 diabetes that was controlled (defined as no more than one hospitalization in the previous six months due to hyperglycemia, hypoglycemia, or ketoacidosis). Female patients could be neither pregnant nor nursing. Peripheral neuropathy had to be shown by the absence of protective sensation from the 5.07 (10g) monofilament pressure test. Included patients had adequate peripheral circulation (ABI > 0.7 and great toe pressure > 0.6) and glycosylated hemoglobin HbA1C < 12 percent. Patients with immunocompromising disease or other disease or treatments that would interfere with the study treatment were excluded.

To be included, ulcers were Grade 1A as defined by The University of Texas Health Services classification of diabetic wounds. A Grade 1A wound is a superficial ulcer not involving tendon, capsule, or bone, without the presence of infection and ischemia.[21] Included ulcers were located on the plantar surface of the foot, between 1cm2 and 12cm2 in size and present for at least 30 days. Absence of osteomyelitis had to be shown clinically and radiographically (negative probe to bone test, plain film radiographs, and magnetic resonance imaging [MRI] if indicated).