The skin is a highly organized, complex organ that consists of two principal outer layers, the epidermis and dermis. The epidermis is the outermost layer and protects the body from invasion and infection and helps to seal in moisture. It constantly proliferates and replaces itself. It does not contain any blood vessels, but instead obtains its oxygen and nutrients from the deeper layers of the skin. The dermis contains blood vessels, nerves, hair roots, and sweat glands. It is also rich in connective tissue that provides elasticity, firmness, and strength. The most important function of dermis is respiration. Wounds that extend only through the epidermis or partially through the dermis are capable of regeneration. If the wound extends through the entire thickness of the dermis, regeneration is no longer possible as there are no cell sources for regeneration. In cases such as full-thickness burns or deep ulcers, surgical solutions have been to apply autologous split-thickness skin grafts from uninjured sites or apply al-logeneic grafts from cadaveric donors. Due to limited availability of donor sites or graft rejections, artificial skin has been pursued as a treatment for burn victims since the 1960s [34]. Since then, several strategies have been developed to create tissue-engineered skin, and three major approaches can be identified: (1) epidermal cells with no dermal layer; (2) only dermal layer; and (3) full-thickness graft, i.e., epidermis and dermis.

Epicel® is an epidermal autograft that consists of cultured keratinocytes on a polyurethane sheet. The polyurethane sheet acts as support for cell growth and application to the wound. Epicel® is grown from a patient's own skin cells and cocultured with mouse cells to form cultured epidermal autografts. Since the grafts are grown from autologous skin cells, they are not rejected by the patient's immune system. From a biopsy of healthy skin about the size of a postage stamp, enough skin can be grown to cover a patient's entire body surface in as little as 16 days. At present, Epi-cel® is the only permanent skin replacement product manufactured in the United States that is commercially available around the world. The shelf life of the grafts is 24 h, which enables the use of these grafts around the world. To date, more than 700 patients have been treated worldwide [35, 36].

Dermagraft® is the first tissue-engineered human fibroblast-derived allogeneic dermal substitute. In this approach, human foreskin-derived fibroblasts are grown on poly(lactide-co-glycolide) (PLGA) sheets. The fibroblasts proliferate to fill the interstices of this biodegradable scaffold and secrete human dermal collagen, matrix proteins, growth factors, and cytokines, to create a three-dimensional human dermal substitute containing living cells. These living skin substitutes are then cryopreserved until use. Dermagraft® has shown success in the treatment of diabetic foot ulcers [37, 38].

Apligraf is a full-thickness graft that consists of allogeneic human keratinocytes and fibroblasts cultured on type 1 bovine collagen matrix. Like human skin, Apligraf® consists of two layers. The lower dermal layer combines bovine type 1 collagen and human fi-broblasts (dermal cells) that produce additional matrix proteins. The upper epidermal layer is formed from human keratinocytes (epidermal cells) that replicate the architecture of the human epidermis. Apligraf® has been used in over 12,000 clinical and commercial applications, and is indicated for the treatment of venous leg ulcers and diabetic foot ulcers [39].

Skin was the first tissue-engineered organ to receive approval by the US Food and Drug Administration (FDA) for clinical applications, and is arguably the most successful example of tissue engineering to date. The aforementioned approaches, among others, have advanced from laboratory studies to clinical trials or commercial applications. Despite this success, there remain some concerns about the use of bovine-derived proteins and the possible risk of infection. Furthermore, tissue-engineered skin is currently limited to selected clinical applications and a truly universal tissue-engineered skin remains to be developed [40].

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