Severe malaria caused by the parasite Plasmodium falciparum is a potentially fatal disease, in part due to the failure of host organs brought about by the accumulation of parasitized red blood cells in the microvasculature. Capillary blockage is associated with the loss of deformability of infected erythrocytes, and in the past, progress in understanding the pathophysiology of these rigidified erythrocytes has been made either by examining postmortem biopsies or by in vitro adhesion studies of suspended infected cells. The PI [unreadable] and colleagues have demonstrated how simple microfluidic devices allow modeling of malaria pathogenesis under controlled laboratory conditions (Shelby et al., 2003, PNAS, 100: 14618-14622). The utility of more advanced microfluidic tools to mimic the mixed cellular environment of capillaries can be tested in relation to two important issues in severe malaria: First, anti-malarial compounds may be prioritized based on their ability to clear obstructed capillaries, not just their antiproliferative activity. Second, parasite clearance by cells of the immune system can be studied under flow and capillary constrictions, which may help understand natural immunity. The defined goal of this R21 project is to develop targeted microfluidic devices for severe malaria: Specific aim I: Evaluate the effect of anti-malarial drugs on clearing capillary obstructions. 1.1. Fabricate microfluidic platforms for the controlled delivery of drugs into a model obstruction. 1.2. Develop high throughput assays for identifying compounds that affect red blood cell deformability. 1.3. Characterize the most promising experimental drugs under fluid flow. Specific aim II: Evaluate phagocytosis of P. falciparum-infected erythrocytes under flow. 2.1. Fabricate microfluidic channels that support host cells. 2.2. Measure phagocytosis in microfluidic channels. 2.3. Develop a model to study pitting in obstructed capillaries. In the future, the devices developed here may also find utility in studying adhesion and natural immunity in malaria, and in control of other infectious diseases. [unreadable] [unreadable]