Development of a human malaria-on-a-chip disease model for drug efficacy and off-target toxicity evaluation

Abstract

AbstractA functional, multi-organ, serum-free system was developed for the culture of P. falciparum in an attempt to establish innovative platforms for therapeutic drug development. It contains 4 human organ constructs including hepatocytes, splenocytes, endothelial cells, as well as recirculating red blood cells which allow for infection with the parasite. Two strains of P. falciparum were used: the 3D7 strain, which is sensitive to chloroquine; and the W2 strain, which is resistant to chloroquine. The maintenance of functional cells was successfully demonstrated both in healthy and diseased conditions for 7 days in the recirculating microfluidic model. To demonstrate an effective platform for therapeutic development, systems infected with the 3D7 strain were treated with chloroquine which significantly decreased parasitemia, with recrudescence observed after 5 days. Conversely, when the W2 systems were dosed with chloroquine, parasitemia levels were moderately decreased when compared to the 3D7 model. The system also allows for the concurrent evaluation of off-target toxicity for the anti-malarial treatment in a dose dependent manner which indicates this model could be utilized for therapeutic index determination. The work described here establishes a new approach to the evaluation of anti-malarial therapeutics in a realistic human model with recirculating blood cells for 7 days.