Advances in tissue engineering and biofabrication for in vitro skin modeling

The global prevalence of skin disease and injury is continually increasing, yet conventional cell-based models used to study these conditions do not accurately reflect the complexity of human skin. The lack of inadequate in vitro modeling has resulted in reliance on animal-based models to test pharmaceuticals, biomedical devices, and industrial and environmental toxins to address clinical needs. These in vivo models are monetarily and morally expensive and are poor predictors of human tissue responses and clinical trial outcomes. The onset of three-dimensional (3D) culture techniques, such as cell-embedded and decellularized approaches, has offered accessible in vitro alternatives, using innovative scaffolds to improve cell-based models' structural and histological authenticity. However, these models lack adequate organizational control and complexity, resulting in variations between structures and the exclusion of physiologically relevant vascular and immunological features. Recently, biofabrication strategies, which combine biology, engineering, and manufacturing capabilities, have emerged as instrumental tools to recreate the heterogeneity of human skin precisely. Bioprinting uses computer-aided design (CAD) to yield robust and reproducible skin prototypes with unprecedented control over tissue design and assembly. As the interdisciplinary nature of biofabrication grows, we look to the promise of next-generation biofabrication technologies, such as organ-on-a-chip (OOAC) and 4D modeling, to simulate human tissue behaviors more reliably for research, pharmaceutical, and regenerative medicine purposes. This review aims to discuss the barriers to developing clinically relevant skin models, describe the evolution of skin-inspired in vitro structures, analyze the current approaches to biofabricating 3D human skin mimetics, and define the opportunities and challenges in biofabricating skin tissue for preclinical and clinical uses.