3D bioprinting of in vitro vascularized skin models and in vivo skin grafts

Abstract Skin, as the outermost layer of human body, serves as a barrier for avoiding external risks. However, skin may easily get injured due to traumatic damage and other diseases. Due to the shortage of donor sites, conventional tissue engineering approaches have been broadly utilized for the formation of tissue-engineered skin. Meanwhile, artificial skin models could also be utilized as a testing platform for pre-clinical studies. However, conventional tissue engineering methods are struggling with the precise control of cell number and allocation, thereby restricting the level of vascularization and failing to fully recapitulate the complexity of native skin. More recently, three-dimensional (3D) bioprinting, on the basis of the advancements of additive manufacturing strategies, has recently appeared as a promising solution to simulate the anatomy and physiology of native skin, thereby providing an alternative fabrication method for vascularized skin models. However, despite technological advances and biomaterial innovations, current 3D bioprinting strategies and biomaterial choices are facing limitations in hierarchical vascular network recapitulation and microenvironment inadequacy for cellular activities. Therefore, this review systematically summarizes the biomaterial systems from natural, synthetic, and composite aspects combined with typical 3D bioprinting strategies from the basic building element, followed with the applications of 3D bioprinted vascularized skin constructs as in vitro skin models and in vivo skin grafts. Although there has been tremendous progress in the reconstruction of vascularized skin models, there remains a substantial gap in the functionality between the currently formed skin models and native skin due to biomaterial limitations, technical hurdles, and the structural and biological complexity of native skin. Herein, the future outlook for the reconstruction of vascularized skin models is discussed and summarized from materials innovations, technical improvements, and artificial intelligence (AI) incorporation.