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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...

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Detalles Bibliográficos
Autores principales: Cairns, Jonathan, Leonard, Emilyanne, Khan, Kainat, Parks, Conor, Maglennon, Gareth, Zhang, Bairu, Lazic, Stanley E., Ewart, Lorna, David, Rhiannon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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
Descripción
Sumario: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.