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Early infection detection
CAMBRIDGE, Mass.—Malaria, a mosquito-transmitted disease that results in high fevers, chills and anemia, is still an endemic issue in many parts of the world. Prevention efforts are helping to slow the spread, and development of vaccine candidates is underway, but there is still room for improvement in detecting malaria in its early stages.
That is the goal of scientists from the laboratories of Anantha Chandrakasan and Subra Suresh at the Massachusetts Institute of Technology (MIT). This team has created an experimental microfluidic device that can detect early- stage malarial infection by streaming a single drop of blood across an electrode that measures a signal distinguishing infected cells from uninfected cells. The research was published Aug. 8 in Lab on a Chip.
The basis of this detection approach focuses on the electrical signatures of infected cells. As noted by the World Health Organization (WHO) on its website, malaria is caused by the parasite Plasmodium falciparum, which is transmitted to humans by mosquitoes. After being infected, the parasites multiply in the liver, then infect red blood cells. When the malaria parasite infects a red blood cell, it becomes more magnetic and rigid. These changes are hard to detect, however, before the parasite matures past the ring stage, which is the earliest stage, and the only one found in circulating blood. Later in the infection, the infected cells stick to small capillaries.
Given those properties, the researchers decided to investigate the possibility of using electrical impedance, a measure of electrical resistance across the cell membrane, as a diagnostic signal. While studies had already examined electrical changes in infected cells in later stages of the disease, it wasn't known if cells in the early, ring stage of infection would demonstrate the same charges.
Sungjae Ha, a graduate student in the Chandrakasan lab, and Sarah Du, a postdoc in the Suresh lab, decided to test this by building a microfluidic device that could measure the magnitude and phase of the electrical impedance of individual cells. Ha and Du are first authors of the study.
The team tested four cell types while optimizing the device: uninfected cells, and infected cells at the ring, trophozoite and schizont stages. Small differences were detected between each, but nothing significant enough to distinguish between stages. They then mathematically combined the measures into an index known as delta, at which point the differences between uninfected cells and infected cells at all three stages became clear.
The current standard for detecting malarial infection is the observation of blood smears under a microscope, and recently there have been some diagnostic tests that detect an antigen to the parasite in the blood. Unfortunately, neither approach has the desired sensitivity. WHO notes on its website that "microscopy remains the mainstay of malaria diagnosis in most large health clinics and hospitals, but the quality of microscopy-based diagnosis is frequently inadequate."
"What's really cool about this device is that it can actually differentiate between uninfected red blood cells and circulating ring infected red blood cells, even though the parasite is still very small at this stage and the host cells have hardly been modified," Matthias Marti, an assistant professor of immunology and infectious diseases at the Harvard School of Public Health, said in a press release. Marti did not participate in the study, but noted this device might also be capable of picking out cells infected with Plasmodium falciparum during its transmission stage.
As development continues, the MIT team is working to integrate the technology into a small, low-cost package. They also plan to investigate whether it could be used to examine the electrical properties of other types of diseased cells to determine if this approach could be used broadly for diagnostics.
"Our hope is that such technologies as those described in this work will ultimately help meet the need for a new generation of portable, disposable and inexpensive diagnostics for a variety of human diseases," said Suresh.
According to WHO, some 3.3 billion people are at risk of malaria. Roughly 219 million cases of malaria were reported in 2010 (with an uncertainty range of 154 million to 289 million), with an estimated 660,000 deaths (with an uncertainty range of 490,000 to 836,000). Fortunately, disease prevention and control measures have reduced malaria death rates by more than 25 percent since 2000.