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The management of complex and severe lower-extremity injuries is challenging for the orthopedic surgeon. When the primary or secondary closure of the defect is not feasible, complex procedures with graft (split-thickness or full-thickness) or flap (pedicled or free) are required. These procedures are performed by specialized plastic surgeons and are at high risk for adverse effects, even high morbidity among both the donor and acceptor sites. Furthermore, split-thickness skin grafts (STSGs) often lead to unsatisfactory results in terms of mechanical stability, flexibility, and aesthetics due to the lack of underlying dermal tissue. Consequently, dermal substitutes, such as MatriDerm (MedSkin Solutions Dr Suwelack AG, Billerbeck, Germany), have been proposed and further developed as a treatment option addressing the management of full-thickness wound defects in conjunction with STSGs. We aimed to present a case of post-traumatic full-thickness wound defect of the left foot after traumatic amputation of the digits that was treated with MatriDerm combined with autologous STSG. In addition, we performed a systematic review of the literature to delineate the efficacy of the use of MatriDerm combined with STSGs in orthopedic cases exclusively.