Compound Absorption in Polymer Devices Impairs The Translatability of Preclinical Safety Assessments.

Organotypic and microphysiological systems (MPS) that can emulate the molecular phenotype and function of human tissues, such as liver, are increasingly used in preclinical drug development. However, despite their improved predictivity, drug development success rates have remained low with the majority of compounds failing in clinical phases despite promising preclinical data. Here, it was tested whether absorption of small molecules to polymers commonly used for MPS fabrication could impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices were fabricated from eight different commonly used MPS polymers and absorption of prototypic compounds with different physicochemical properties were analyzed. It was found that overall absorption is primarily driven by compound hydrophobicity and the number of rotatable bonds. However, absorption can differ by >1000-fold between polymers with polydimethyl siloxane (PDMS) being most absorptive whereas polytetrafluoroethylene (PTFE) and thiol-ene epoxy (TEE) absorbed the least. Strikingly, organotypic primary human liver cultures successfully flagged hydrophobic hepatotoxins in lowly absorbing TEE devices at therapeutically relevant concentrations whereas isogenic cultures in PDMS devices were resistant, resulting in false negative safety signals. Combined, these results can guide the selection of MPS materials and facilitate the development of preclinical assays with improved translatability. This article is protected by copyright. All rights reserved.