Translation of a Human-Based Malaria-on-a-Chip Phenotypic Disease Model for In Vivo Applications.

Abstract

In 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.