Microengineering
Targets Malaria


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Unlike other tropical diseases, malaria continues to confound researchers searching for a cure to a disease that affects 10% of the world's population, kills some one million people per year, and debilitates millions more. Seeking a vaccine or drug that will kill the malaria parasite before it is able to fully develop, scientists at the University of South Florida, Tampa, FL, and Draper Laboratories, Cambridge, MA, are collaborating to build a device that mimics the human liver, the spot where the parasite settles after it enters the body. Bioengineering teams using microfluidic devices to build a three-dimensional structure on which to grow cells hope to study the growth and development of the parasite in its dormant stage, where it is easier to target and, theoretically, destroy.

Specifically, researchers are going after Plasmodium Vivax, one of the disease's two strains, found primarily outside of Africa. P. falciparum is the strain generally found in sub-Saharan Africa, where most malaria-caused deaths occur. "Vivax is a more subtle form of the disease," says Dr. John Adams, principal investigator with USF's global infectious disease research team. "But it probably has more of an economic impact." It occurs in older people, "often people trapped in the grip of poverty and affects their ability to work," he says. Collectively, the disease critically impacts economies of tropical developing countries.

The microfluidic device is small enough to host six tests that can be run parallel to each other, greatly increasing the volume of testing that can be done from current media. Photo Credit: University of South Florida

Malaria research historically has centered on P. falciparum because it is more lethal. But now the Bill and Melinda Gates Foundation, with a goal of eliminating the disease entirely, has stepped in to the fight against vivax with a $5.45-million grant won by the USF-Draper team. The sum may seem small in relation the foundation's multibillion endowments but it fills a void. For a disease that affects 90 million to 300 million people, "It is poorly understood," says Adams.

A 3-D Platform

Malaria parasite P. vivax seen in a cell culture beneath a microscope. Photo Credit: Draper Laboratory

"This is one of the most exciting projects to come along in a long time," says Joseph Cuiffi, principal investigator with the Draper Bioengineering Center at USF, in Tampa. "It is truly an interdisciplinary project," requiring a range of professional expertise, including biologists, biomedical engineers, fabrication engineers, chemical engineers, and others.

Researchers will use microfluidic devices developed by Draper over the past 10 years to grow cells on a 3-D platform designed to support complex tissue growth, in this case akin to a human liver. The device is a microscope slide-sized chip containing channels and chambers through which cells grow and fluid flow is maintained by a standard syringe pump. The medium differs from standard 2-D surfaces of a petri dish, and also offers improvement over animal models, which also differ from humans in how the disease is contracted, says Adams.

That's important because liver cells tend to stop metabolizing after a few days in the more standard media, preventing researchers from observing the full development of the parasite in the dormant stage.

The technology, previously unavailable in a lab setting, also offers economies of scale, enabling multiple tests to be conducted during the same time period. The volume of tests that can be conducted in parallel dwarfs current methods and conditions in vivo or in animals, say researchers.

Technology Mimics Body

Researchers are focusing on drugs to destroy vivax in the liver because that is where the parasite lands after being introduced to the bloodstream through a mosquito bite. There, it remains dormant for at least three weeks and in extreme cases years, after which it reproduces, ruptures liver cells, and explodes into the bloodstream.

There are fewer parasites–hundreds or a few thousand–in the liver at the initial stage of human infection. Those numbers multiply to the millions when the parasite escapes into the bloodstream and reproduces, the stage at which symptoms occur. Drugs are available to treat bloodstream stages but they do not work in the liver, notes Adams. He says there now is only one drug that works on the disease in the liver but it comes with potentially debilitating side effects. Destroying the parasite in the liver would essentially prevent vivax and the possibility of transmission.

"To eradicate malaria you have to kill it in the dormant stage," says Adams. "But we know little about this stage of the parasite."

"We need to see parasites infect live cells over 21 days or more," notes Cuiffi.

The microfluidic devices each have enough space to hold six tests that will run parallel to each other over a three-week period. "There's a confluence of physical properties," says Adams. "The idea is to mimic what is in the body."

Together with the USF-Draper team, the project includes researchers from a number of institutions around the globe with skills to maintain long-term blood cultures. The vivax strain of malaria has proven to be very difficult to grow in laboratories. "To be able to replicate and study the entire malaria infection process outside the body will be critical in developing new drugs with the potential to eliminate malaria," says Draper's Cuiffi.

To eradicate malaria you have to kill it in the dormant stage. But we know little about this stage of the parasite.

John Adams, principal investigator, University of South Florida

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June 2011

by John Kosowatz, Senior Editor, ASME.org