Abstract: The authors reviewed 22 patients who received living skin equivalent (LSE) (Apligraf®, Organogenesis, Inc., Canton, Massachusetts) over 20 months in whom conventional therapy had failed. Ten patients had chronic venous insufficiency, and six patients had ulcers caused by venous stasis, diabetes mellitus, and arterial insufficiency. The remaining ulcers were attributed to connective tissue disease, trauma, radiation, cryoglobulinemia, and necrobiotic xanthogranuloma. Eight patients were diabetic. The mean duration of ulceration before LSE placement was 15 months. The mean ulcer size was 48mm. Patients were followed up weekly for eight weeks and then monthly for at least 22 months. Fourteen patients healed completely; treatment failed in eight.

Introduction

Nonhealing lower-extremity ulcers are a major cause of physical disability and diminished quality of life. In addition, persistent ulcers have an enormous impact on the use of healthcare resources.

A bioengineered living skin replacement (LSE), (Apligraf®, Organogenesis Inc., Canton, Massachusetts) has been approved by the US Food and Drug Administration (FDA) for use with standard therapeutic compression in the treatment of noninfected partial- and full-thickness skin ulcers due to venous insufficiency of longer than one month’s duration that have not responded adequately to conventional ulcer therapy. LSE has also received FDA approval for use in patients with diabetic foot ulcers, principally full-thickness neuropathic diabetic foot ulcers of more than three weeks duration that have failed conventional ulcer therapy and extend through the dermis but without tendon, muscle, capsule, or bone exposure.

Although the utility of LSE has been evaluated in the specific management of hard-to-heal venous and diabetic foot ulcers, data are limited regarding general applicability of this therapy for ulcers that are multifactorial or from other distinct causes. To evaluate further the efficacy of LSE in management of all hard-to-heal ulcers, the authors retrospectively reviewed their experience during a 20-month period.

Methods

This study was approved by the institutional review board. All patients who received LSE for chronic ulcers that failed conventional therapy were included. All patient demographic, treatment, and graft site outcome information was collected in a retrospective manner. The following variables were examined: wound measurements, duration of ulceration, cause of ulceration, and response to prior treatment. In addition to clinical assessments and wound measurement, sequential photographs were taken to document ulcer changes. Patients who denied authorization were not included.

Lse was used only after conventional therapeutic methods failed. Patients who had clinically infected wounds or known allergies to bovine collagen did not receive this therapy. The wound was prepared in a sterile fashion. LSE was applied directly to the wound surface. The LSE was smoothed on the wound surface with a cotton applicator to remove air pockets and wrinkles, and excess Lse was trimmed from the wound edge. A nonadherent three-layer dressing was placed over the wound bed. The wound was inspected weekly from Weeks 1 through 8 and then monthly with continued observation to at least 22 months. Wound closure was defined as 100-percent epithelization without drainage. Device failure was defined as persistent ulceration or failure to engraft.

Results

The mean age of the 22 patients in this study was 67 years (range, 28–102 years). Twelve patients (54%) were men. Nine patients (40%) were hypertensive, 10 (45%) had coronary artery disease, five (23%) had hyperlipidemia, and seven (32%) were grossly obese. Five patients (23%) continued to smoke. Ten patients (45%) had chronic venous insufficiency, and two (9%) were diagnosed as having connective tissue disease.

The causes of the chronic ulcers were chronic venous insufficiency in 10 (45%) or multifactorial in six (27%). The other ulcers were from trauma in one (5%), connective tissue disease in two (9%), radiation in one (5%), cryoglobulinemia in one (5%), and necrobiotic xanthogranuloma in one (5%). The mean duration of ulceration before LSE placement was 15 months (range, 2–84 months). The mean ulcer size was 48mm (range, 13–165mm) (Table 1).

Table 1

Of 22 patients, 14 (64%) had ulcers that healed completely and eight (36%) failed to heal. Seventy percent of the patients with chronic venous ulcers, who constituted nearly half the patient population studied, had their ulcers healed with LSE application. Of the ulcers that healed completely, the time to healing ranged from 1 to 22 months (mean, 5 months) (Figure 1). The suspected causes of failure to heal were edema, obesity, infection, ischemia, noncompliance, medication (corticosteroids), duration of ulceration before LSE treatment, and ulcer size. The cause of failure appeared to be variable with no clear majority cause found. Overall, LSE was tolerated well with no observed adverse effects.

Figure 1

This chart shows the time from living skin equivalent treatment to healing.

Discussion

This study has several findings that have important clinical implications. First, LSE was an effective treatment for some of the recalcitrant ulcers studied. Second, this study expands prior studies in patients with chronic ulcers from multiple causes.[1] Finally, LSE is a well-tolerated therapy, with no adverse effects noted in this study group.

Over the past decade, advances in biotechnology have led to the availability of skin substitutes to treat chronic ulcers and wounds. Although the mechanism of healing is not completely understood, previous reports have suggested that skin substitutes interact with underlying tissue, producing cytokines and growth factors to promote wound healing.[2] This study, in a single center during a 20-month period, confirms data from other reports that LSE is an effective treatment of recalcitrant ulcers after standard treatment fails.[3]

Within the study group, the reasons for treatment failure were many. Two patients in whom therapy failed had either a large ulcer or an ulcer of prolonged duration. These characteristics have been reported previously as risk factors for treatment by Margolis, et al.[4] The cause of failure in another patient was infection. Some investigators advocate routine culture of ulcers before application of LSE in an effort to prevent this complication.

No adverse reactions to Lse occurred in the study group. Skin hypersensitivity reactions and LSE rejection are uncommon. In a multicenter prospective study of 293 randomly assigned patients treated with an allogeneic bilayered human skin equivalent for their venous ulcers, no clinical evidence of rejection or immune sensitization was observed.[5]

Limitation

This study was retrospective and conducted in a single center. It was not powered to ascertain treatment benefits for different ulcer etiologies and did not focus on the number of LSE applications in individual patients. However, these data represent long-term treatment outcomes of various ulcer etiologies encountered in a tertiary wound-care center and, therefore, have clinical relevance.

Conclusions

LSE was a useful adjunctive therapy for the chronic ulcers studied. This therapy should be considered in patients with chronic ulcers that have failed conventional therapy. Although this case series is small, the results suggest that LSE may be beneficial in ulcers from multiple causes, including treatment of atypical ulcers.[6] Future studies may determine the long-term efficacy of LSE in multifactorial ulcers and wounds.