@article{2591,
  keywords = {bone marrow, experimental design, flow cytometry, organ on a chip, toxicity testing},
  author = {Jonathan Cairns and Emilyanne Leonard and Kainat Khan and Conor Parks and Gareth Maglennon and Bairu Zhang and Stanley E. Lazic and Lorna Ewart and Rhiannon David},
  title = {Optimal experimental design for efficient toxicity testing in microphysiological systems: A bone marrow application},
  abstract = {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.},
  year = {2023},
  journal = {Frontiers in Pharmacology},
  volume = {14},
  pages = {1142581},
  month = {2023},
  issn = {1663-9812},
  doi = {10.3389/fphar.2023.1142581},
  language = {eng},
}