Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application

Frontiers in Pharmacology

Pharmacology

Stanley E. Lazic¹  Jonathan Cairns¹  Bairu Zhang¹  Emilyanne Leonard²  Kainat Khan³  Conor Parks³  Gareth Maglennon⁴  Rhiannon David⁵  Lorna Ewart⁶ 

[1] Data Sciences and Quantitative Biology, Discovery Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;Integrated Bioanalysis, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;Oncology Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;Pathology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;Safety Innovation, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;Safety Platforms, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, United Kingdom;

关键词: organ on a chip;    experimental design;    toxicity testing;    bone marrow;    flow cytometry;   

DOI  :  10.3389/fphar.2023.1142581

 received in 2023-01-11, accepted in 2023-02-21,  发布年份 2023

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

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Copyright © 2023 Cairns, Leonard, Khan, Parks, Maglennon, Zhang, Lazic, Ewart and David.