Using a full thickness bioengineered human skin equivalent as a model for radiation biology research.

Radiation exposure from radiological or nuclear events, medical treatments, or spaceflight poses significant health risks, yet human-specific models to investigate radiation effects on skin remain limited. This study establishes a novel in vitro platform using a full-thickness bioengineered human skin equivalent colonized with natural mixed human microbiota (coHSEs) to assess radiation-induced biological responses. We exposed coHSEs to acute doses of up to 4 Gy with x-rays and evaluated their viability, structural integrity, and molecular responses over 25 days. The coHSE model demonstrated sustained viability without dose-dependent opportunistic microbial overgrowth when procedural optimizations were applied. Radiation-induced epidermal remodeling did not compromise tissue architecture or swabbing-based sample collection. Cell proliferation analyses revealed dose- and time-dependent dynamics, with consistent dermal cell density maintained across radiation doses. Comparative multi-omic analyses, including untargeted metabolomics, targeted lipidomics, and 16 S metagenomics, revealed conserved metabolic and microbial responses to radiation in both coHSEs and skin from irradiated mice. Enriched pathways such as arachidonic acid and fatty acid metabolism, along with shifts in microbial taxa including Lachnospiraceae, support the translational relevance of the coHSE model. This system offers a scalable, ethical, and physiologically relevant platform for radiation biology, biodosimetry, and therapeutic development, advancing terrestrial health research with promising application for space research.