Advanced human skin platform for accelerated bioactive discovery

Summary: Abstract Body: Natural product (NP) libraries are a critical source for discovering bioactives in cosmetic, dermatological, and medicinal applications. However, identifying and characterizing novel bioactives from crude materials remains challenging, necessitating biologically complex, and long-lasting skin models capable of capturing subtle molecular and cellular changes. To address these gaps, we developed an advanced human skin platform with the longevity, complexity, and sensitivity required for comprehensive bioactive discovery for skin health. This platform maintains the cellular and structural integrity of human skin within bioengineered culture inserts, supporting extended viability up to one month. Histological and immunohistochemical analyses (e.g., H&E, keratin 5, keratin 10, and filaggrin staining) confirmed sustained tissue integrity and healthy morphology throughout the culture period. This platform has been applied to various applications, including anti-aging, inflammation, and celluar senescence studies, utilizing diverse human skin donors and experimental conditions. For instance, inflammatory models were induced using lipopolysaccharides (LPS), tumor necrosis factor alpha (TNF-alpha), or cytokine cocktails (e.g., IL-17/IL-22) and tested with compounds like clobetasol propionate, epigallocatechin gallate, and fisetin, which showed dose-dependent reductions in pro-inflammatory cytokines and associated gene expression changes. Additionally, extracts from plant-, endophyte-, and marine-derived NP libraries were screened and compared against known tool compounds. Each skin sample generated over 30,000 multi-modal data points, integrating biochemical, transcriptomic, histological, and functional analyses. This data-rich platform provides deep mechanistic insights, enhances clinically relevant efficacy assessments, and bridges critical gaps in longevity, complexity, and scalability. It represents a transformative tool for advancing bioactive discovery and accelerating the development of safer, more effective solutions for skin health. Kyung-Jin Jang¹, Chris Hinojosa¹, Sunghoon Lee¹, Purnendu Sharma¹, Paige Thompson¹, Bailey Coates¹ 1. Outer Biosciences, Malden, MA, United States. Translational Studies: Preclinical