Design principles for composition and performance of cultured skin substitutes.

Engineering of skin substitutes provides a prospective source of advanced therapies for treatment of acute and chronic skin wounds. Hypothetically, engineering of skin substitutes can allow deliberate fabrication of biologic materials with properties that address specific patho-biologic conditions (e.g., burns, scars, cutaneous ulcers, congenital anomalies). By design and incorporation of specific therapeutic properties in skin substitutes, reduction of morbidity and mortality from full-thickness skin wounds may be facilitated. Morbidity from grafting of autologous, split-thickness skin [1] occurs at both the treatment site and the donor site [2]. Acute wounds that require grafting include excised burns, burn scars, and congenital cutaneous anomalies (i.e. giant nevus). Patients with acute wounds, in general, do not have healing impairment, but may not have sufficient donor sites to cover their wounds if large total body surface areas (TBSA) are involved. Estimates for hospitalizations from burns range from 60 000–80 000 annually, and costs for recovery from acute injuries range from US$36 000–117 000 per patient [3–5]. Increased availability of skin grafts would prospectively provide advantages over conventional therapy including, but not limited to: reduction of donor site area required to close wounds permanently; reduction of surgical procedures and hospitalization time; grafting of patients who are poor candidates for donation of skin grafts; reduction of mortality and morbidity from scarring; and delivery of genetically-modified cells [6–10]. The ultimate objective for skin substitutes is restoration of the anatomy and physiology of uninjured skin after treatment and healing of the wound. At present, only autologous full-thickness skin grafts, free flaps or pedicle flaps [11,12] restore all of the structures and functions of uninjured skin but donor sites and treatment sites must be equal in size. Tissue expanders can stretch skin by an approximate factor of 2, but are associated with complications including rupture or infection of the expander, and necrosis of expanded skin before transplantation [13]. Meshed split-thickness skin grafts may be expanded by ratios of 1:4 with characteristic scarring of mesh interstices. Skin substitutes that contain cultured cells can provide large quantities of grafts for wound treatment, but restore only a subset of anatomic structures and physiologic functions of skin. Therefore, the full potential for engineering of skin substitutes has not yet been realized.