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Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application
Introduction: Microphysiological systems (MPS; organ-on-a-chip) aim to recapitulate the 3D organ microenvironment and improve clinical predictivity relative to previous approaches. Though MPS studies provide great promise to explore treatment options in a multifactorial manner, they are often very c...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103791/ https://www.ncbi.nlm.nih.gov/pubmed/37063297 http://dx.doi.org/10.3389/fphar.2023.1142581 |
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author | Cairns, Jonathan Leonard, Emilyanne Khan, Kainat Parks, Conor Maglennon, Gareth Zhang, Bairu Lazic, Stanley E. Ewart, Lorna David, Rhiannon |
author_facet | Cairns, Jonathan Leonard, Emilyanne Khan, Kainat Parks, Conor Maglennon, Gareth Zhang, Bairu Lazic, Stanley E. Ewart, Lorna David, Rhiannon |
author_sort | Cairns, Jonathan |
collection | PubMed |
description | Introduction: Microphysiological systems (MPS; organ-on-a-chip) aim to recapitulate the 3D organ microenvironment and improve clinical predictivity relative to previous approaches. Though MPS studies provide great promise to explore treatment options in a multifactorial manner, they are often very complex. It is therefore important to assess and manage technical confounding factors, to maximise power, efficiency and scalability. Methods: As an illustration of how MPS studies can benefit from a systematic evaluation of confounders, we developed an experimental design approach for a bone marrow (BM) MPS and tested it for a specified context of use, the assessment of lineage-specific toxicity. Results: We demonstrated the accuracy of our multicolour flow cytometry set-up to determine cell type and maturity, and the viability of a “repeated measures” design where we sample from chips repeatedly for increased scalability and robustness. Importantly, we demonstrated an optimal way to arrange technical confounders. Accounting for these confounders in a mixed-model analysis pipeline increased power, which meant that the expected lineage-specific toxicities following treatment with olaparib or carboplatin were detected earlier and at lower doses. Furthermore, we performed a sample size analysis to estimate the appropriate number of replicates required for different effect sizes. This experimental design-based approach will generalise to other MPS set-ups. Discussion: This design of experiments approach has established a groundwork for a reliable and reproducible in vitro analysis of BM toxicity in a MPS, and the lineage-specific toxicity data demonstrate the utility of this model for BM toxicity assessment. Toxicity data demonstrate the utility of this model for BM toxicity assessment. |
format | Online Article Text |
id | pubmed-10103791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-101037912023-04-15 Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application Cairns, Jonathan Leonard, Emilyanne Khan, Kainat Parks, Conor Maglennon, Gareth Zhang, Bairu Lazic, Stanley E. Ewart, Lorna David, Rhiannon Front Pharmacol Pharmacology Introduction: Microphysiological systems (MPS; organ-on-a-chip) aim to recapitulate the 3D organ microenvironment and improve clinical predictivity relative to previous approaches. Though MPS studies provide great promise to explore treatment options in a multifactorial manner, they are often very complex. It is therefore important to assess and manage technical confounding factors, to maximise power, efficiency and scalability. Methods: As an illustration of how MPS studies can benefit from a systematic evaluation of confounders, we developed an experimental design approach for a bone marrow (BM) MPS and tested it for a specified context of use, the assessment of lineage-specific toxicity. Results: We demonstrated the accuracy of our multicolour flow cytometry set-up to determine cell type and maturity, and the viability of a “repeated measures” design where we sample from chips repeatedly for increased scalability and robustness. Importantly, we demonstrated an optimal way to arrange technical confounders. Accounting for these confounders in a mixed-model analysis pipeline increased power, which meant that the expected lineage-specific toxicities following treatment with olaparib or carboplatin were detected earlier and at lower doses. Furthermore, we performed a sample size analysis to estimate the appropriate number of replicates required for different effect sizes. This experimental design-based approach will generalise to other MPS set-ups. Discussion: This design of experiments approach has established a groundwork for a reliable and reproducible in vitro analysis of BM toxicity in a MPS, and the lineage-specific toxicity data demonstrate the utility of this model for BM toxicity assessment. Toxicity data demonstrate the utility of this model for BM toxicity assessment. Frontiers Media S.A. 2023-03-31 /pmc/articles/PMC10103791/ /pubmed/37063297 http://dx.doi.org/10.3389/fphar.2023.1142581 Text en Copyright © 2023 Cairns, Leonard, Khan, Parks, Maglennon, Zhang, Lazic, Ewart and David. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Cairns, Jonathan Leonard, Emilyanne Khan, Kainat Parks, Conor Maglennon, Gareth Zhang, Bairu Lazic, Stanley E. Ewart, Lorna David, Rhiannon Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title | Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title_full | Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title_fullStr | Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title_full_unstemmed | Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title_short | Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application |
title_sort | optimal experimental design for efficient toxicity testing in microphysiological systems: a bone marrow application |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103791/ https://www.ncbi.nlm.nih.gov/pubmed/37063297 http://dx.doi.org/10.3389/fphar.2023.1142581 |
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