Spleen-inspired device to clear blood of sepsis-causing pathogens

Microfluidics experts at Harvard’s Wyss Institute have made another big splash, expanding their reputation for creating useful devices that mimic organ function. Recent research funded by DARPA has yielded an impressively effective portable dialysis-like technology to treat sepsis. The device clears blood of pathogens by adding magnetic beads coated with a human protein that recognizes many bacterial (and some fungal) carbohydrates, which are then removed from the blood (in complexes with pathogens) by magnets that pull them across narrow channels into an adjacent stream of saline.

Magnetic beads in artificial spleen
Magnetic beads bound to S. aureus (left) and E. coli (right). Pseudocolored scanning electron micrographs. From Nature News, “Artificial spleen cleans up blood.”

Sepsis is a major public health challenge; its mortality rate is 30–50% even in leading treatment centers. The first line of treatment is usually intravenous broad-spectrum antibiotics, but these are only effective if the pathogen is susceptible. As antibiotic-resistant strains become more prevalent, the need for alternative therapies is increasingly urgent.

The Wyss team’s solution seems simple—bind pathogens and filter them out—but the device’s success relies on some smart tweaks. For example, the protein on the beads’ surface (mannose-binding lectin, MBL) was engineered to only bind pathogens; its pro-inflammatory and pro-clotting functions were removed. Further, thoroughly removing the magnetic beads from blood while maintaining a clinically feasible filtration rate requires a precise ratio of flow rates, for which the researchers took inspiration from the spleen. Analysis of filtered blood in initial experiments revealed not-insignificant quantities of magnetic beads remaining, so lead author Joo Kang and colleagues ingeniously added large, uncoated magnetic beads to collect the smaller ones that do not bind pathogens.

Microfluidic spleen
Cartoon schematic; in the device, blood and saline flow through many channels in parallel. Opsonin refers to a pathogen-binding bead. From Kang J et al., Nature Med 2014.

The device clears ~90% of live S. aureus and E. coli from septic rats’ blood within 1 h and reduces lethality from >80% to ~10%. Removal of pathogens by this process also improves respiratory rate and partially restores leukocyte levels, suggesting that it would speed patient recovery.

While the MBL-coated beads are effective in clearing some fungi and a large proportion of microbes in complex cecal mixtures, the device likely will not be effective against all sepsis pathogens. For example, MBL does not bind Pseudomonas aeruginosa or Haemophilus influenzae, both of which can cause sepsis. Perhaps additional beads bearing other pathogen-binding proteins such as toll-like receptors (or fragments thereof) could be added to broaden the range of pathogens that could be cleared. Another challenge to the development of this device is the large difference in scale between the rats employed in the study and humans.