An Overview on the Manufacturing of Functional and Mature Cellular Skin Substitutes

There are different types of skin diseases due to chronic injuries that impede the natural healing process of the skin. Tissue engineering has focused on the development of bioengineered skin or skin substitutes that cover the wound, providing the necessary care to restore the functionality of injured skin. There are two types of substitutes: acellular skin substitutes, which offer a low response to the body, and cellular skin substitutes (CSSs), which incorporate living cells and appear as a great alternative in the treatment of skin injuries due to their greater interaction and integration with the rest of the body. For the development of a CSS, it is necessary to select the most suitable biomaterials, cell components, and methodology of biofabrication for the wound to be treated. Moreover, these CSSs are immature substitutes that must undergo a maturing process in specific bioreactors, guaranteeing their functionality. The bioreactor simulates the natural state of maturation of the skin by controlling parameters such as temperature, pressure, or humidity, allowing a homogeneous maturation of the CSSs in an aseptic environment. The use of bioreactors not only contributes to the maturation of the CSSs but also offers a new way of obtaining large sections of skin substitutes or natural skin from small portions acquired from the patient, donor, or substitute. Based on the innovation of this technology and the need to develop efficient CSSs, this work offers an update on bioreactor technology in the field of skin regeneration. Impact Statement The manufacture of functional cellular skin substitutes (CSSs) is one of the current goals in the field of tissue engineering to improve the treatment of chronic skin injuries, thus favoring skin repair and regeneration. The main advances in the development of innovative and effective CSSs are largely focused on the selection of more adequate cellular components, biomaterials, and biofabrication techniques to be used in their biofabrication. However, the maturation of CSSs should be an essential step in obtaining a functional substitute capable of replacing the native skin. The sequential procedure from the design of the CSS to its maturation process will be reviewed. In the context of the manufacturing of novel CSSs, different technologies to biofabricate functional structures and how their maturation can be carried out by specific devices are addressed, as well as key challenges facing the design and development of CSSs.