02305nas a2200373   4500000000100000000000100001008004100002653002600043653001200069653003100081653002000112100002100132700002100153700002300174700002200197700002100219700001800240700001500258700002200273700002100295700002400316700002700340700002000367700001800387700001600405700002000421700002100441245010100462856006700563300001100630490000800641520126800649022001401917                                       d10aPlasmodium falciparum10amalaria10amicrophysiological systems10aorgan-on-a-chip1 aMichael J. Rupar1 aHannah M. Hanson1 aBrianna L. Botlick1 aNarasimhan Sriram1 aStephanie Rogers1 aJustin Zuniga1 aZhanhe Liu1 aSteven J. Trimmer1 aJoseph M. Ciurca1 aChristopher J. Long1 aChristopher W. McAleer1 aStephan Schmidt1 aPaola Favuzza1 aPhilip Lowe1 aNathalie Gobeau1 aJames J. Hickman00aTranslation of a Human-Based Malaria-on-a-Chip Phenotypic Disease Model for In Vivo Applications  uhttps://onlinelibrary.wiley.com/doi/abs/10.1002/advs.202505206  ae052060 vn/a3 aIn 2023 malaria claimed ≈600000 lives, with 90% of those deaths attributed to the Plasmodium falciparum parasite. This resurgence in mortality emphasizes the necessity of adopting alternative models to accelerate therapeutic development. The Malaria-on-a-Chip model used here incorporated human liver, spleen, and endothelium with P. falciparum-infected blood, and was maintained for 7 days using serum-free medium. This model sustained all stages of the intraerythrocytic life cycle and allowed for organ–organ interaction, providing advantageous preclinical insight into malaria pathophysiology. Chloroquine, lumefantrine, or artesunate were delivered as monotherapies to 3D7 or W2-infected systems. Dose-dependent parasite clearance was observed in both strains for all compounds. Recrudescence occurred in the 3D7-infected model following treatment with chloroquine or lumefantrine, but not artesunate. In W2-infected systems, chloroquine and lumefantrine treatment resulted in parasitemia stabilization by day 7, while artesunate further reduced parasitemia. Population dynamics modeling of pharmacokinetic and pharmacodynamic (PK/PD) outcomes were utilized to predict human in vivo parameters for efficacy and off-target toxicity using in vitro results.  a2198-3844