Epidermal skin substitutes

Epidermal skin substitutes are cultured keratinocytes taken as a biopsy either from the patient (autograft) or from another human (allograft) and then expanded and enlarged in a laboratory setting. They are manufactured as sheets, gels, sprays, and suspensions, although only cultured epidermal autograft sheets are currently available in the U.S.

One of the first skin substitutes on the market is Epicel (Genzyme, Cambridge, Mass., USA), a cultured epidermal autograft which is indicated for patients with deep dermal to full-thickness burns affecting 30% or greater total body surface area. Epicel is not used in chronic wound care. The main advantage of Epicel in burn care is the ability to cover large wounds with permanent skin that will not be rejected because the graft is autologous (Kamolz, 2008). Enough skin to cover the patient’s entire body can be ready within 4 weeks. Disadvantages to Epicel include the 2-3 week wait for product availability and its fragility. It is only 2-8 cells thick so can be difficult to handle and apply. It also lacks long-term strength which can lead to spontaneous blistering months after grafting (Woodley et al, 1998). Table 19-1 lists other epidermal skin substitutes that are not yet available in the United States.

Dermal skin substitutes

Dermal substitutes contain fibroblasts seeded and cultured on a bioabsorbable matrix, along with the ECM proteins and growth factors that they produce. They may be delivered fresh or cryopreserved, although only the latter is available in the U.S.

Dermagraft (Advanced Biohealing, Westport, Conn., USA) is a cryopreserved allogeneic dermal substitute with fibroblasts seeded on a bioabsorbable polyglactin mesh (Roberts and Mansbridge, 2002). Once thawed at the bedside in an easy step-by-step process, a 5- × 7.5-cm living dermal substitute can be applied onto clean, debrided wounds that are free of infection.

Dermagraft has demonstrated efficacy in the treatment of patients with diabetic foot ulcers (Gentzkow et al, 1999; Pollak et al, 1997). In a randomized controlled trial of 314 patients with diabetic foot ulcers of over 6 week’s duration, 30% of Dermagraft-treated patients were healed at 12 weeks versus 18.3% in the control group (p = .023) (Marston et al, 2003). Dermagraft is approved by the U.S. Food and Drug Administration (FDA) for the treatment of full-thickness diabetic foot ulcers of greater than 6 weeks duration which extend through the dermis, and are without tendon, muscle, joint capsule or bone exposure. It is also recommended for use in the treatment of nonhealing diabetic foot ulcers by the Wound Healing Society (Steed et al, 2006).

Dermagraft must be used only as an adjunct to standard care, which includes off-weighting the ulcer, debridement, treatment of infection, glucose control, and assurance of adequate blood flow for healing. Optimal healing rates are associated with aggressive offloading, not only with footwear but also with crutches or wheelchairs. Dermagraft is applied with either side toward the wound bed and is covered with a nonadherent contact layer. To ensure good contact of Dermagraft with the wound bed, the wound should be lightly filled with saline-moistened gauze or a soft foam dressing. Although Dermagraft was applied weekly for up to 8 weeks in clinical trials, this frequent application should not be necessary with most patients. The best-practice algorithms published for Apligraf (Figures 19-1 and 19-2) provide excellent guidelines for the use of any skin substitute in the clinical setting (Cavorsi et al, 2006).

FIGURE 19-1 Best practice algorithm for the use of Apligraf® in the treatment of venous leg ulcers.

(From Cavorsi J et al: Best-practice algorithms for the use of a bilayered living cell therapy (Apligraf®) in the treatment of lower-extremity ulcers, Wound Rep Regen 14:102-109, 2006.)

FIGURE 19-2 Best practice algorithm for the use of Apligraf® in the treatment of diabetic foot ulcers. ABI, Ankle-brachial index.

(From Cavorsi J et al: Best-practice algorithms for the use of a bilayered living cell therapy (Apligraf®) in the treatment of lower-extremity ulcers, Wound Rep Regen 14:102-109, 2006.)

Bilayered skin substitutes

Apligraf (Organogenesis, Canton, Mass., USA) is a living allogeneic bilayered skin substitute consisting of keratinocytes and fibroblasts. Fibroblasts are cultured in a type 1 bovine collagen gel. Keratinocytes are then seeded on this gel, cultured, and air exposed to stimulate differentiation into the layers of the epidermis, including the stratum corneum. This process results in a 44-cm², 0.75-mm-thick skin substitute delivered fresh on a Petri dish containing nutrient medium, and sealed in an airtight bag.

Apligraf, when used in conjunction with compression therapy, has been demonstrated to achieve closure of hard-to-heal venous ulcers at a significantly higher rate than seen with compression alone (Falanga and Sabolinski, 1999; Falanga et al, 1998). Apligraf is FDA-approved for the treatment of venous ulcers of greater than 1 month duration that have not adequately responded to standard care, including debridement, infection control, assurance of adequate arterial flow, and compression therapy. National guidelines support the use of bi-layered skin substitutes in conjunction with compression bandaging to improve healing rates of venous ulcers (Robson et al, 2006).

Apligraf has also demonstrated efficacy in the treatment of diabetic foot ulcers. In a trial of 208 patients with diabetic neuropathic foot ulcers, Veves et al (2001) found that 56% of patients treated with Apligraf were healed at 12 weeks versus 38% in the control group (p = .0042). Apligraf is FDA-approved for the treatment of diabetic neuropathic foot ulcers of at least 3 weeks duration that extend through the dermis without tendon, muscle, joint capsule, or bone exposure and which have not adequately responded to standard care, including debridement, infection control, glucose control, off-weighting, and assurance of adequate arterial flow.

Like Dermagraft, Apligraf is an adjunct to standard wound care. Apligraf is applied to the wound with the dermal side contacting the wound bed. Many clinicians fenestrate Apligraf with a scalpel prior to application to allow exudate to pass through it onto bandages because pooled exudate under the product may decrease its efficacy. Once applied, it should be anchored with Steri-strips, staples, or skin adhesive. Apligraf should be covered with a nonadherent contact layer and a secondary bandage of choice. Foam dressings work well over venous ulcers because they absorb exudate and apply local pressure under the compression wrap to keep the Apligraf in good contact with the wound bed. Secondary dressings are changed as needed based on the amount of exudate, but the contact layer over the Apligraf should not be disturbed for at least 2 weeks. Any wound cleansing over the ensuing few weeks should be very gentle so as not to disturb any lingering allogeneic cells. Figures 19-1 and 19-2 give algorithms for the use of Apligraf in the clinical setting.

OrCel (Forticell Bioscience, New York, NY, USA) is a bilayered allogeneic product first developed by an Australian physician in the 1980s to treat his son, who suffered from epidermolysis bullosa. Outcomes were improved when OrCel was used in combination with split-thickness autografts in the surgical reconstruction of children with epidermolysis bullosa–related hand contractures and syndactyly (Eisenberg and Llewelyn, 1998). In 2001, the FDA approved the fresh version of OrCel under a humanitarian device exemption (HDE) for the treatment of surgical wounds and donor sites in patients with epidermolysis bullosa undergoing reconstructive hand surgery. Cryopreserved OrCel was later approved with an HDE for the same indication. In a study of split-thickness autograft donor site treatment in burn patients, donor sites treated with Orcel healed an average of 7 days faster versus treatment with Biobrane-L (p < .0006) and were ready for recropping for more autografts an average of 5 days faster (Still et al, 2003). The fresh version of OrCel was FDA approved for the treatment of donor sites in burn patients in 2001. Cryopreserved OrCel has been studied in venous ulcer treatment (unpublished) and FDA approval for this indication is pending. Neither version of Orcel is currently available.

Cadaveric human skin has been used for years as temporary wound coverage in burn care (Britton-Byrd et al, 2008; Kagan et al, 2005). This nonliving product facilitates the short-term coverage of large tissue defects when autografts are not yet available, leading to reduced loss of fluid, electrolytes, and protein, decreased risk of infection, decreased wound desiccation and pain, and improved success of later autografting. One disadvantage of using cadaveric skin is the possibility of disease transmission, despite donor screening regulations by the FDA and quality control standards developed by the American Association of Tissue Banks (AATB) (Humphries and Mansavage, 2006). Another disadvantage is the fact that cadaveric skin is rejected by the host within 2 to 4 weeks. Cadaveric human skin is available fresh (used within 14 days of harvesting), cryopreserved (stored in a freezer for 3–6 months or in liquid nitrogen for up to 10 years), or irradiated (stored at room temperature).

GammaGraft (Promethean LifeSciences, Pittsburgh, Penn., USA) is gamma-irradiated human cadaver skin that provides wound coverage for chronic wounds or burns. It can remain in place until the wound is healed, depending on wound size and depth of tissue damage. GammaGraft is placed on a clean, debrided wound that is free of infection and is covered with a nonadherent dressing for 1 to 2 days. At that time, the graft should be adhered to the wound base. If the graft is not adherent, the wound may be infected, and the graft should be removed. If GammaGraft is adherent, it should be left uncovered; it will dry out and appear much like a scab. It is left in place while new host skin covers the wound underneath. As the wound heals, the edges of the GammaGraft will peel away and can be cut off. Treatment of the underlying problem, such as compression for edema or off-weighting for pressure redistribution, must be continued throughout the treatment period. GammaGraft may be used on any chronic wound. However, although there are case reports of GammaGraft use in chronic wounds (Rosales et al, 2003), no randomized controlled trials have demonstrated the efficacy of this product in wound healing compared to standard care.

Additional products for providing cell therapy in the treatment of chronic wounds are in development (Ehrenreich and Ruszczak, 2006; Hrabchak et al, 2006). Next-generation products may extend beyond the relative simplicity of providing keratinocytes and/or fibroblasts with their secreted growth factors and ECM proteins to a chronic wound. Melanocytes for repigmentation, endothelial cells for neovascularization, stem cells for regeneration of tissue all may be included in future products. Genetically engineered cells may be used that express specific growth factors to stimulate a particular aspect of wound healing (e.g., neovascularization) identified to be deficient in an individual patient. “Smart” skin substitutes may be developed in which genetically engineered cells respond to the wound environment by secreting or restricting secretion of certain cytokines, depending on what the wound requires to progress through repair, or better yet, regeneration (Metcalfe and Ferguson, 2007). Cells can be engineered to secrete increased levels of natural bactericidal chemicals to decrease risk of infection (Schurr et al, 2009). As these products become available, clinicians must critically analyze data to ensure that the use of these products enhances healing while reducing complications compared with standard care.