The fundamental skin role is to supply a supportive barrier to protect body against harmful agents, fluid loss, and injuries. Three layers of skin including epidermis, dermis, and hypodermis form a sophisticated tissue composed of extracellular matrix (ECM) mainly made of collagens and glycosaminoglycans (GAGs) as a scaffold, different cell types such as keratinocytes, fibroblasts, melanocytes, and endothelial cells embedded in the ECM. When the skin injured, depends on its severity, the majority of mentioned components are recruited in order to wound regeneration. Additionally, different growth factors like fibroblast growth factor, epidermal growth factor, and vascular endothelial growth factor are needed for orchestrated wound healing process through four phases called damage limitation, inflammatory, proliferative, and remodeling. In case of large surface area wounds, natural wound repair seems inefficient. Inspired by nature, scientists in tissue engineering area attempt to engineered constructs mimicking natural healing process to promote skin restoration in untreatable injuries. There are three main types of commercially available engineered skin substitutes including epidermal, dermal, and dermoepidermal one, and each of them could be composed of scaffold, desired cell types or growth factors which could be autologous, allogeneic, or xenogeneic. Moreover, they may be cellular, usually keratinocyte and fibroblasts, or acellular substitutes. They are used to accelerate wound healing and recover normal skin functions with pain relief.The most commercially available skin substitutes include Epicel™, Integra®, and ApligrafTM. Epicel™ as an epidermal equivalent is composed of sheets of autologous keratinocytes lain on a petrolatum gauze support which is removed one week after transplantation. Integra™ is an acellular dermal substitute composed of a porous cross-linked bovine collagen, chondroitin-6-sulfate GAG, and a synthetic silicone polymer. Apligraf® is a bilayer skin substitute. Its epidermal layer contains bovine type I collagen and dermal layers includes cultured keratinocytes and fibroblasts obtained from neonatal foreskin. Although there are a wide variety of commercially available skin substitutes, almost none of them could meet all qualifications required for a natural skin including deep skin appendages (e.g. hair follicles, sebaceous and sweat glands), appropriate vascularization, temperature and pressure sensation, and even pigmentation