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Microfiltering Sepsis

A microfluidic device may effectively filter out pathogens that trigger septic shock.

Each year, intensive care units in the United States hospitalize nearly 750,000 patients with severe sepsis, a syndrome that manifests when a body’s immune system overreacts to infection. As sepsis sets in, inflammation rapidly spreads through the body, often shutting down organs and potentially leading to death. Antibiotics are often the main course of treatment, but there’s a lag time before the drugs kick in, during which inflammation continues to spread.

Blood filter for sepsis: A microfluidic prototype selectively draws out infectious pathogens as blood flows through. The top image shows blood flow from left to right through the device. Without a magnetic field (top), red blood cells (red) and pathogens (yellow) pass in and out of the device together. In the presence of a magnet (bottom), the pathogens bind to magnetic beads (green), separating from blood into different channels. Researchers say that such a device may help clean large volumes of blood, particularly in cases of severe sepsis.

Now scientists at Children’s Hospital Boston are developing a miniature filtration device that can rapidly pump blood out of the body, clearing it of infectious agents before delivering the blood back to the body. Principal investigator Donald Ingber says that the microfluidic device can be used in combination with antibiotics as a first line of defense in treating sepsis before the antibiotics take effect.

“The goal is to clear the blood in a period of hours,” says Ingber. “You really have a tipping point, and we want to try to get over that point so that the antibiotics can kick in.”

Ingber and his collaborators from Harvard Medical School, Boston University, and the Charles Stark Draper Laboratory have designed a prototype that is able to pull pathogens out of blood as it flows through a microscopic filtration system. Ingber says that the device improves on current blood filtration methods such as hemodialysis. Dialysis machines filter blood by pumping it out through a catheter and into a compartment with a semipermeable membrane. On the other side of the membrane is a compartment with fluid flowing in the opposite direction. Via forces of diffusion and osmosis, small, unwanted molecules from blood cross the membrane, exiting with the fluid as the filtered blood flows back into the body.

While dialyzers can filter small molecules out of blood, larger molecules such as pathogens are too big to cross. Instead, Ingber and his colleagues designed a small microfluidic device that pulls these larger pathogens out of blood.

The device itself contains a pair of microscopic channels–one for blood, the other for a saline-based solution. The two channels meet in a central compartment. The idea is to give the saline solution properties that will selectively draw pathogens out of blood as the two fluids mix.

However, because of their very small scale, microfluidic devices have no moving parts that can mechanically mix fluids together. Even as they come in contact, fluids will remain discrete, retaining their respective molecules. Then Ingber hit upon the idea to use a small magnetic field. He first identified specific molecules that naturally bind to certain pathogens related to sepsis. Ingber and his colleagues then coated these molecules with tiny magnetic beads in solution. They then pumped the solution through one channel as infected blood was pumped through the other. As the two channels funneled into one compartment, the team turned on a small magnet on the side of the magnetic bead solution. As the fluids came in contact, the pathogens from the blood bound with the magnetically coated molecules, which in turn were pulled toward the magnet, away from the blood flow.

Ingber modeled the design in theory after the spleen, which contains molecules that bind to pathogens, ferrying them out of the body as blood flows through.

So far, the team has been able to filter a volume of blood comparable to that found in a premature baby within two hours. The researchers are currently working to increase the device’s capacity and efficiency, and they plan to use more pairs of channels to increase the filtration rate. The Center for Integration of Medicine and Innovative Technology (CIMIT) recently awarded the team a $500,000 grant toward further developing the technology, and Ingber plans to use the funds to set up animal studies in the next year.

“We’re going to try this approach in rabbits, because they are the same size as preemies, who often have life-threatening sepsis,” says Ingber. “And we’re hoping that if we can demonstrate survival in rabbits, we can quickly go to patients.”

Ultimately, Ingber envisions incorporating the microfluidic device into a cartridge form, which can be snapped into any conventional hemofiltration or dialysis system.

Jeffrey Platt, a professor of surgery at the University of Michigan Medical School, says that one challenge in using such a device is anticipating the specific pathogen involved in a given case of sepsis. There are multiple infectious agents, bacterial and fungal, that could trigger septic shock, and researchers would have to devise different magnetically coated solutions for each pathogen. However, Platt says, the device may effectively treat other conditions outside of sepsis.

“The concept underlying the device is novel and interesting, and might ultimately find other applications, such as removal of malignant cells or cholesterol particles from the blood,” says Platt. “Whether in fact it would find one or another use depends on what may be found when it is tested in whole animal systems.”

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