Friday, August 17, 2007

Bioengineered Skin Substitutes (BSS)

Tissue engineered skin substitutes emerged in the 1980s. Development was motivated primarily by the critical need for early coverage of extensive burn injuries in patients with insufficient sources of autologous skin for grafting. Since then, skin substitutes have been widely used to address the prevalent problem of chronic wounds associated with non-burn etiologies (such as hard-to-heal, chronic, open wounds in patients with diabetes mellitus and /or arteriosclerosis). The annual incidence of serious burns in the United States is estimated at 70,000. The prevalence of venous leg ulcers is between 600,000 and 1,500,000; and 15 to 20 percent of people with diabetes eventually suffer a chronic foot wound. The direct cost, in the US, of dressings alone for all these conditions has been estimated at over $5 billion per year. photo credit
In the past wound management was essentially passive: to remove impediments to wound healing (e.g., uncontrolled diabetes mellitus, infection, and ischemia) and allow nature to take its course. Today, while not ignoring these basics, the approach seeks to actively intervene and improve upon natural healing using such modalities as hyperbaric oxygen, electrical stimulation, skin surface negative pressure, exogenous growth factors and bioengineered skin substitutes. Thus, a "one-size-fits-all" approach, whereby a clinician would use his favorite dressing on most wounds, has given way to individualization of therapy based upon the physiology of each particular patient and wound. It is very challenging to understand the relative merits and roles of each available technology. So I thought I would try to review some of the various commercial skin substitutes.
Important criteria for a biosynthetic skin substitute include: rapid and sustained adherence to the wound surface (most important), impermeable to exogenous bacteria, allow water vapor transmission similar to normal skin, inner surface structure that permits cell migration/proliferation/in-growth of new tissue, flexible and pliable so it can conform to irregular wound surfaces, resistant to linear and shear stresses, biodegradable (important for "permanently" implanted membranes), low cost, indefinite shelf life, minimal storage requirements, absence of antigenicity, and absence of local/systemic toxicity.
Biobrane®, Biobrane-L®is a bilayer temporary wound dressing. The outer epidermal analog is constructed of an ultrathin silicone film with barrier functions comparable to skin. It has small pores that allow for exudate removal and permeability of topical antibiotics. The inner dermal analog is composed of a three dimensional irregular nylon filament weave upon which type I collagen peptides are bonded. It is removed after re-epithelialization or prior to skin graft on excised wound. It has a long shelf life and can be stored at room temporature. It is clinically indicated in superfical to mid-partial thickness burns (debrided of nonviable tissue), excised burn wounds with or without meshed autografts, donor sites, and partial thickness skin slough disorders. Biobrane adheres firmly to the wound. It provides a barrier to evaporative water loss, avoids desiccation of wound tissue, provides a barrier to bacteria, optimizes healing environment, decreases pain from the wound, decrease wound exudate, is durable/flexible/non-toxic, and is permeable to topical antibiotics.

Tips for its use: Select appropriate wounds. Apply biobrane under modest tension, and secure to surrounding intact wound edge Apply gentle gauze pressure dressing. Immobilize for 24-36 hrs on a flat wound surface and 48 hrs over a joint surface. Change outer gauze dressings as needed until plasma leak stops. Aspirate fluid or bubbles. If there is increasing exudate, biobrane must be removed--switch to topical agent. Sulfamylon solution can be applied to burn wound surface if early infection suspected. Wait until biobrane appears opaque and dry before removing. If pain or bleeding is encountered, stop and wait several more days before removing.
TransCyte® is a bilayer temporary wound dressing. It's outer epidermal analog is a thin nonporous silicone film. It's inner dermal analog is layered human fibroblast products (collagen type I, fibronectin, glycosaminoglycan). It is removed after re-epithelization or prior to skin grafting. It must be kept frozen until use. It is used clinically for mid-dermal indeterminate partial thickness burns with viable wound surface, for excised burn wounds with viable wound surface, and for donor sites.

Tips for use: Select appropriate wounds (will not adhere to non-viable tissue). Apply to clean wound bed and apply gauze compression dressing. Immobilize for 24 hrs, longer over joints. Aspirate fluid and air bubbles. Remove when dry and opaque (as with Biobrane).

Integra® is a dermal analog of biodegradable wound care device comprised of a porous matrix of cross-linked bovine tendon collagen and glycosaminoglycan. The epidermal analog is a thin semi-permeable polysiloxane (silicone) layer that provides environmental barrier protection and water vapor loss similar to skin. The collagen-glycosaminoglycan biodegradable matrix provides a scaffold for cellular invasion and capillary growth. After the neodermis formation, the epidermal analog (silicone) is removed and replaced with a thin epidermal autograft or cultured epithelial cells. Major causes of loss of the dermal analog are infection and shearing with devascularization. It is stored in 70% isopropyl alcohol.

Apligraf, is supplied as living bilayered, cell therapy. It's dermal analog is a collagen matrix populated with fibroblasts which have produced a dermal layer. These dermal elements are obtained from neonatal foreskin. The epidermis is a stratified and multilayer providing a biologic barrier function. The epidermis is also obtained from neonatal foreskin. The foreskin is decontaminated with antibiotics, antifungals, and an ethyl alcohol rinse. Production of cell stocks involves enzymatic digestion of the foreskin tissue and fibroblast/keratinocyte isolation. Apligraf is made by a process that take 20 days. There is a 7 day shipping window. It is individually packaged for use in a nutrient medium and sealed in a polybag. It is shipped overnight via courier. Keep Apligraf in the sealed poly bag, inside the shipping container at 20C-23C; 68F-73F, until use.

OrCel® is a composite living skin (bilayered) equivalent. It is described as comprising an epidermal layer of cultured keratinocyte cells, a layer of non-porous collagen, and a dermal layer of cultured fibroblast cells in a porous cross-linked type I bovine collagen sponge matrix. Donor dermal fibroblasts are cultured on and within the porous collagen sponge side of the collagen matrix while keratinocytes (epidermal layer), from the same donor, are cultured on the coated, non-porous side of the collagen matrix. It serves as an absorbable biocompatiable matrix. OrCel®'s first FDA approvals were obtained last year for treatment of acute surgical excisions, such as contracture release sites and donor sites in Epidermolysis Bullosa, patients undergoing hand reconstruction surgery, and donor sites in burn victims undergoing excision and autografting. Since the cells used to produce Orcel are extensively expanded in vitro, they cease to express significant levels of HLA-II antigens and, upon application to a wound bed, are apparently not immediately recognized by the recipientís immune system as foreign. Cryopreserved OrCel® can provide off-the-shelf wound treatment, available on demand at point of use. This device should be stored in a clean, dry location at room temperature. To use prepare wound area using standard methods to ensure wound is free of debris and necrotic tissue.

Cultured epithelial autograft (CEA) is an epidermal layer replacement only. It uses cell culture technology to grow a small sample of the patient's own keratinocytes up to 10,000 fold in surface area. It takes 2-3 weeks to grow the desired amount. It can be applied over an excised wound or over incorporated allograft dermis (Integra). If used alone, the epidermal-wound junction has an incomplete basement membrane and very low resistance to sheer forces. There is a 28-50% take on excised wounds and a 45-75% take on invorporated allograft dermis.

Alloderm® is not a bilayer product and acts strictly as a dermal transplant. It is an acellular dermal matrix derived from donated human skin tissue supplied by US AATB-compliant tissue banks utilizing the standards of the American Association of Tissue Banks (AATB) and Food and Drug Administration's (FDA) guidelines. Since AlloDerm is regarded as minimally processed and not significantly changed in structure from the natural material, the FDA has classified it as banked human tissue. When AlloDerm is prepared, the human donor tissue undergoes a multi-step proprietary process that removes both the epidermis and the cells that can lead to tissue rejection and graft failure, without damaging the matrix. Once the dermal tissue has been decellularized, the final step is preservation. The processed tissue matrix is preserved with a patented freeze-drying process that prevents damaging ice crystals from forming. The cells responsible for immune response and graft rejection are removed. What remains is a matrix or framework of the natural biological components, which allows the body to mount its own tissue regeneration process. It requires an application of a thin epithelial autograft.

The OASIS® Wound Matrix is a biologically derived extracellular matrix-based wound product that is compatible with human tissue. OASIS is unique because it is a complex scaffold that provides an optimal environment for a favorable host tissue response, a response characterized by restoration of tissue structure and function. OASIS is comprised of porcine-derived acellular small intestine submucosa. OASIS® Wound Matrix is indicated for the management of wounds, including diabetic ulcers, venous ulcers, partial and full-thickness wounds, pressure ulcers, chronic vascular ulcers, trauma wounds, draining wounds, and surgical wounds. It has a 2 yr shelf lift at room temperature. To use in a "wet" wound, hydrate the Oasis with saline after applying to the wound, cover with a non-adherent dressing, then an absorptive dressing (ie calcium alginate), and then secure in place. For a dry wound, hydrate the Oasis with saline after applying to the wound, cover with a non-adherent dressing, then Hydrogel, and then secure into place. The optimum secondary dressing is determined by wound location, size, depth, and user preference. Change the secondary dressing as needed to maintain a moist, clean wound area. Frequency of secondary dressing change will be dependent upon volume of exudate produced and type of dressing used. As healing occurs, sections of OASIS may gradually peel and may be removed during dressing changes. Do not forcibly remove sections of OASIS that may adhere to the wound. Alternatively, OASIS may form a caramel-colored gel, which can be rinsed away with gentle irrigation. On inspection, if OASIS is no longer covering the wound, place an additional piece of OASIS over the wound.

Safety: "BSS, namely Biobrane®, TransCyte®, Dermagraft®, Apligraf®, autologous cultured skin, and allogeneic cultured skin, are at least as safe as biological skin replacements or topical agents/wound dressings. The safety of Integra® could not be determined, nor could the long-term safety of BSS with respect to viral infection and prion disease."

Efficacy: "In managing partial thickness burns, BSS, namely Biobrane®, TransCyte®, Dermagraft®, and allogeneic cultured skin, are at least as efficacious as topical agents/wound dressings or allograft. Apligraf® combined with autograft is at least as efficacious as autograft alone. In managing full thickness burns, the efficacy of autologous cultured skin could not be determined, nor could the efficacy of Integra®."

Other References

Use of Skin

New Skin for Old Developments in Biological Skin Substitutes; Arch Dermatol. 1998;134:344-349

Current Concepts in Wound Healing; Plastic and Reconstructive Surgery Suppliment; Vol 117, No 75, June 2006.

Wound Healing: Skin Substitutes and Blood-Derived Growth Factors --Medical Policy BCBS

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