From left: Sungjae Ha and Anantha Chandrakasan demonstrate the chip in the Nanomechanics Laboratory. Photo: Patricia Sampson/EECSResearchers at Massachusetts Institute of Technology (MIT) have found a way to detect early-stage malarial infection of blood cells by measuring changes in the infected cells’ electrical properties.

The scientists, from the laboratories of MIT’s Anantha Chandrakasan and Subra Suresh—who is now president of Carnegie Mellon Univ.—have built an experimental microfluidic device that takes a drop of blood and streams it across an electrode that measures a signal differentiating infected cells from uninfected cells. The work, published in Lab on a Chip, is a first step toward a field-ready, low-cost, portable malaria-detection device.

“Ultimately the goal would be to create a postage stamp-sized device with integrated electronics that can detect if a person has malaria and at what stage,” says Chandrakasan, the Joseph F. and Nancy P. Keithley Prof. of Electrical Engineering and a principal investigator at MIT’s Microsystems Technology Laboratories (MTL), who specializes in developing low-power electronic devices. Similar diagnostics may be applicable to other infections and diseases.

Sorting out the signals
When the malaria parasite Plasmodium falciparum infects a red blood cell, the cell becomes more magnetic and more rigid, properties that can be detected in a rapid-diagnostic device. But these changes are hard to detect before the parasite matures beyond the ring stage—its earliest stage, and the only stage found in circulating blood. At later stages of infection, the infected red blood cells adhere to small capillaries, blocking circulation and causing various symptoms, and even death in severe cases.

So the researchers decided to look into using electrical impedance as a diagnostic signal. Several types of infection, including malaria, alter a cell’s impedance, a measure of electrical resistance across the cell membrane. Studies had already measured electrical changes in later-stage infected cells, but it wasn’t clear that cells that had reached only the ring stage of infection would exhibit electrical changes.

To find out, first authors Sungjae Ha, a graduate student in the Chandrakasan laboratory, and Sarah Du, a postdoctoral researcher in the Suresh laboratory (also known as the Nanomechanics Laboratory), built a microfluidic device capable of measuring the magnitude and phase of the electrical impedance of individual cells. The device is essentially a cell-counting device, similar in approach to other low-cost, portable devices being developed to diagnose illnesses such as HIV.

The challenge, however, involved optimizing the electronics to allow very accurate measurements of impedance for each cell as it passes by. The researchers had to minimize interfering electric signals from the substrate the blood flows over and prevent the cells from sticking to one another.

In tests of cells of four cell types—uninfected cells and infected cells at the ring, trophozoite and schizont stages—the device detected small differences in measures of magnitude and seemingly random differences in phase, but not quite enough to definitively differentiate among stages.

However, by mathematically combining the measures into an index called delta, the differences between uninfected cells and all three stages became clear.

Solving real-world problems
Malaria is a curable disease, but diagnosis remains a challenge. This ability to discern the circulating parasite’s stage from a drop of blood opens the possibility of building a device that could be used to rapidly diagnose malarial infection in places where laboratories and skilled medical personnel are scarce.

Traditionally, technicians detect malarial infection visually, by observing blood smears through a microscope. More recently, the World Health Organization has supported the use of rapid diagnostic tests that detect an antigen to the parasite in the blood. These tests provide results in about 15 min and do not require skilled technicians, so sick people can be diagnosed and treated on the spot.

But neither of these approaches is very sensitive.

The collaborative MIT team of experts in microfluidics, circuit design, materials science and microbiology has designed their new cell-differentiating technology so that it can be packaged as a low-cost device, but more work needs to be done.

Source: Massachusetts Institute of Technology