A Novel Perfused Full‐Thickness Human Skin Microphysiological System for Modeling Injury, Regeneration, Tumor Pathophysiology, and Therapeutics Development

Translating preclinical research findings to clinical applications presents challenges due to the metabolic and anatomical disparities between animal models and humans. Although organ-on-a-chip models replicate the organization of human cells, they lack the complexity of the microenvironment and anatomical fidelity. Developing alternative research models with greater physiological and anatomical relevance to humans holds the potential to enhance translational success and reduce reliance on animal experimentation. In this study, we have showcased the technical details and conditions to maintain the viability of ex vivo perfused large human abdominal fasciocutaneous flaps for up to three weeks. Our efforts involved refining surgical procedures, vascular territory mapping (angiosome analysis), and pedicle exploration; engineering the bioreactor system; and optimizing perfusion media. Angiography via thermal and fluorescent methods was used to confirm the perfusion success. Metabolic activity was closely monitored by tracking glucose consumption and lactate production. Assessments of tissue viability encompassed histological analysis, TUNEL staining, gene expression profiling, measurement of vascular and metabolic reactivity, and in vitro propagation of isolated adipose stem cells and dermal fibroblasts. Furthermore, we harnessed our optimized human skin perfusion model to investigate the dynamics of radiation and chemical-induced injuries. Additionally, we explored the model's utility in studying adipose tissue metabolism and employed human skin tissue to establish melanoma and breast cancer tumor models. To our knowledge, this is the first model capable of preserving the function and viability of a large flap for extended periods, providing a proof-of-concept foundation for diverse research applications.