In April 1997, Apligraf® (Novartis), an in vitro construct of human skin (human skin equivalent HSE1), gained approval from the HPB in Canada for use in healing venous leg ulcers. This was the first major regulatory body to approve HSE for this indication. Awaiting approval in several other countries, Apligraf® is the first bilayered (epidermal-dermal), in vitroengineered, skin tissue commercially available for clinical use. Apligraf® is also under investigation in clinical trials for various cutaneous surgical wounds, burns, and diabetic foot ulcers.2
Apligraf® is the most recent addition to a family of bioengineered skin healing agents which includes Dermagraft-TC® (Advanced Tissue Sciences, Smith & Nephew) and Integra Artificial Skin® (Integra Life Sciences Corp.).
Apligraf, Novartis, human skin equivalent, HSE, leg ulcers
Indications for Use
- Venous leg ulcers’ Canadian approval was granted April 1997. Approval was based on safety and efficacy data from the largest multicentre, parallel group, randomized clinical trial ever conducted in venous leg ulcers.3 Studies in North America suggest that 1-3% of the population suffer from venous leg ulcers, particularly the population over age 60. Other causes of leg ulcers include diabetic or other neuropathies and arterial insufficiency.
Apligraf® represents the culmination of several recent advances in tissue culture techniques.2 It has been engineered using serially passaged human epidermal keratinocytes and human dermal fibroblasts, cells obtained from neonatal foreskin, with a matrix of acid dissociated type I bovine collagen. The overlying epidermis is developed on the surface of the dermal matrix and when a monolayer of epidermal cells is formed, the HSE is raised to the air-liquid interface to generate a protective cornified layer. Serum is not necessary for the development of the epidermis. HSE is strong and has handling characteristics similar to split-thickness skin allowing it to be meshed, stapled, and sutured.4
Clinical Studies in Venous Ulcers
Interim results from a prospective, controlled, parallel group, multicentre trial in 233 patients with venous ulcers are interesting.1 All patients entered into this trial had failed on previous venous ulcer treatments, the median duration of ulcers was approximately one year, and the median size of the treated ulcers was approximately 400 mm.4
Weekly visits for eight weeks with one mid-week visit the first week. Patients received up to five applications to their venous ulcers during the first three weeks of treatment. The Apligraf® was held firmly in place with a multilayered compression wrap and the active control group also received a multilayered compression bandage. After eight weeks, patients were placed in elastic stockings. If healing had not occurred, the bandaging technique was continued for up to six months. All patients were followed for one year with visits scheduled at three-month intervals.2,4 Practical details on how best to use this new product are important and will be detailed in Part II of this article in the next issue of the Letter.
Median time to 100% wound closure was 57 days with active treatment versus 181 days for standard care (P=0.0066). Of the 127 actively treated patients, 78 (64.1%) achieved complete wound closure, while only 47 of 109 (44.3%) of the control patients achieved 100% closure (P=0.012).1
Mechanism of Action
Unknown, but contact between the wound bed and human fibroblasts in the dermal layer of HSE seems to send out physiologic signals for wound repair.3 In many patients, HSE promotes new tissue growth at the wound edge. In others, it appears to take like any graft, rapidly integrating into surrounding tissue. Over time, HSE is replaced by the patient’s own skin cells.3
Clinical trials have found no sign of toxicity in over 352 HSE treated patients, and there have been no reports of allergic reactions or immunological responses with initial or repeated use.3 This product is said to have a safety profile similar to traditional wound-healing methods. Both the maternal donor blood and donor cells from neonatal foreskin are meticulously screened and certified free of CMV, hepatitis A, B and C, Epstein-Barr virus, and other infectious agents.3
Novartis have worldwide marketing rights. The cost of a 7.5 cm round disk will be approximately $950 Canadian. Usually only one treatment is needed.
HSE has a number of clinical advantages. Unlike much autografting, treatment with HSE does not necessitate hospitalization,3 and unlike other bioengineered skin alternatives, HSE has a well-defined stratum corneum. HSE contains both dermal fibroblasts and an epidermal sheet, with their commensurate cytokine and growth factor capabilities and natural biologic interaction. It also provides a collagenous matrix and a natural protective covering, the stratum corneum. It therefore has the potential to not only promote healing via different mechanisms (primary take, protective covering, growth factors2) but also serve as a source of new tissue.4
Preliminary results suggest that Apligraf® will improve the treatment of venous ulcers. It is also undergoing clinical trials to assess its benefit in other areas of wound care (burns, diabetic ulcers) and following dermatological surgery procedures (post-micrographic surgery wounds, etc.).2
“Apligraf® is ideal for patients whose leg ulcer has persisted for more than three months. Once the underlying cause of ulceration is corrected, HSE provides the structural and physiological properties of human skin that promote healing in chronic leg wounds.”
Dr G. Sibbald, Toronto
- Sabolinski ML, Alvarez O, Auletta M et al. Cultured skin as a ‘smart material’ for healing wounds: experience in venous ulcers. Biomaterials 1996; 17: 311-320.
- Sibbald G. Personal communication. May, 1997
- Wilkins LM, Watson SR, Prosky SF et al. Development of a bilayered living skin construct for clinical applications. Biotechnology and Bioengineering 1994; 43: 747-756.