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      Compound Absorption in Polymer Devices Impairs the Translatability of Preclinical Safety Assessments

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          Abstract

          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 most compounds failing in clinical phases despite promising preclinical data. Here, it is tested whether absorption of small molecules to polymers commonly used for MPS fabrication can impact preclinical pharmacological and toxicological assessments and contribute to the high clinical failure rates. To this end, identical devices are fabricated from eight different MPS polymers and absorption of prototypic compounds with different physicochemical properties are analyzed. It is 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 are 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.

          Abstract

          Identical microdevices are fabricated from eight different polymers and it is found that absorption of prototypic compounds with different physicochemical properties differs by >1000‐fold between materials. Using 3D human liver cultures, it is shown that minimizing absorption can improve the accuracy of pharmacological or toxicological testing. These results have important implications for improving preclinical assay accuracy in drug development.

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          Most cited references78

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          The origins and the future of microfluidics.

          The manipulation of fluids in channels with dimensions of tens of micrometres--microfluidics--has emerged as a distinct new field. Microfluidics has the potential to influence subject areas from chemical synthesis and biological analysis to optics and information technology. But the field is still at an early stage of development. Even as the basic science and technological demonstrations develop, other problems must be addressed: choosing and focusing on initial applications, and developing strategies to complete the cycle of development, including commercialization. The solutions to these problems will require imagination and ingenuity.
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            Solvent compatibility of poly(dimethylsiloxane)-based microfluidic devices.

            This paper describes the compatibility of poly(dimethylsiloxane) (PDMS) with organic solvents; this compatibility is important in considering the potential of PDMS-based microfluidic devices in a number of applications, including that of microreactors for organic reactions. We considered three aspects of compatibility: the swelling of PDMS in a solvent, the partitioning of solutes between a solvent and PDMS, and the dissolution of PDMS oligomers in a solvent. Of these three parameters that determine the compatibility of PDMS with a solvent, the swelling of PDMS had the greatest influence. Experimental measurements of swelling were correlated with the solubility parameter, delta (cal(1/2) cm(-3/2)), which is based on the cohesive energy densities, c (cal/cm(3)), of the materials. Solvents that swelled PDMS the least included water, nitromethane, dimethyl sulfoxide, ethylene glycol, perfluorotributylamine, perfluorodecalin, acetonitrile, and propylene carbonate; solvents that swelled PDMS the most were diisopropylamine, triethylamine, pentane, and xylenes. Highly swelling solvents were useful for extracting contaminants from bulk PDMS and for changing the surface properties of PDMS. The feasibility of performing organic reactions in PDMS was demonstrated by performing a Diels-Alder reaction in a microchannel.
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              Clinical development success rates for investigational drugs.

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                Author and article information

                Contributors
                reza.zandi.shafagh@ki.se
                volker.lauschke@ki.se
                Journal
                Adv Healthc Mater
                Adv Healthc Mater
                10.1002/(ISSN)2192-2659
                ADHM
                Advanced Healthcare Materials
                John Wiley and Sons Inc. (Hoboken )
                2192-2640
                2192-2659
                10 December 2023
                26 April 2024
                : 13
                : 11 ( doiID: 10.1002/adhm.v13.11 )
                : 2303561
                Affiliations
                [ 1 ] Department of Physiology and Pharmacology Karolinska Institutet Stockholm 17177 Sweden
                [ 2 ] Dr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology 70376 Stuttgart Germany
                [ 3 ] University of Tuebingen 72074 Tuebingen Germany
                [ 4 ] Division of Micro‐ and Nanosystems KTH Royal Institute of Technology Stockholm 10044 Sweden
                [ 5 ] Department of Oncology and Pathology Science for Life Laboratory Karolinska Institutet Stockholm 17165 Sweden
                [ 6 ] Department of Drug Metabolism and Pharmacokinetics (DMPK) Merck KGaA 64293 Darmstadt Germany
                Author notes
                Author information
                https://orcid.org/0000-0002-1140-6204
                Article
                ADHM202303561
                10.1002/adhm.202303561
                11469150
                38053301
                57debd7a-588a-488e-945f-3b61e59337ff
                © 2023 The Authors. Advanced Healthcare Materials published by Wiley‐VCH GmbH

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 07 November 2023
                Page count
                Figures: 6, Tables: 2, Pages: 13, Words: 8925
                Funding
                Funded by: Horizon 2020 Framework Programme , doi 10.13039/100010661;
                Award ID: 875510
                Funded by: Knut och Alice Wallenbergs Stiftelse , doi 10.13039/501100004063;
                Award ID: VC‐2021‐0026
                Funded by: Vetenskapsrådet , doi 10.13039/501100004359;
                Award ID: 2021‐02801
                Categories
                Research Article
                Research Articles
                Custom metadata
                2.0
                April 26, 2024
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.4.9 mode:remove_FC converted:11.10.2024

                drug development,logp,microphysiological system,polymer‐drug interaction,small molecule absorption

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