Taking advantage of recent advances in nanotechnology and microfluidics, researchers have made significant progress toward a device that could be used to rapidly remove pathogens from the blood of patients with sepsis, a potentially life-threatening condition that occurs when an infection is distributed throughout the body via the bloodstream.
The new system effectively acts as an artificial spleen, filtering the blood using injectable magnetic nanobeads engineered to stick to microörganisms and toxins. After the beads are injected, blood is removed and run through a device that uses a magnetic-field gradient to extract the nanobead-bound germs. Then the blood is returned to the body.
Engineers at Harvard University’s Wyss Institute for Biologically Inspired Engineering, where the technology is under development, are also hoping the device will be able to identify the specific microörganism causing the problem, which could help physicians determine the most effective antibiotic treatment more quickly than they can with conventional diagnostic tests.
At a scientific conference at Harvard Medical School last week, Donald Ingber, one of the technology’s inventors and the director of the of the Wyss Institute, said his group has been encouraged by preliminary results from tests of the blood-cleansing therapy in rats. The institute recently announced that it would apply money from a $9.25 million contract with the Defense Department’s Advanced Research Projects Agency (DARPA) toward helping “accelerate its translation to humans as a new type of sepsis therapy.”
Sepsis, which kills millions of people worldwide each year, occurs when chemicals the body releases to fight an infection in the bloodstream trigger an inflammatory response throughout the body. The worst cases can lead to the failure of multiple organs. Since any one of a range of organisms can cause the problem, a patient believed to have sepsis is usually given a so-called broad-spectrum antibiotic while doctors culture the blood in attempt to identify the specific organism at fault so they can prescribe the specific antibiotic that will target it. This process can take several days.
But the broad-spectrum antibiotic doesn’t always work, and in many cases the blood culture fails to identify the pathogen. Meanwhile, delaying the administration of the proper drug by mere hours can significantly reduce a patient’s chance of survival. “Studies have shown that every hour a patient receives the wrong antibiotic—even a strong broad-spectrum antibiotic—mortality increases by 5 to 9 percent,” says Ingber.
Sepsis is also a leading killer of soldiers in combat. To address this problem, DARPA is aiming to develop a portable “dialysis-like” therapy that would quickly cleanse blood that has been removed from the body and then return it. The desired technology would be capable of removing many different types of pathogens and would function without the need for anticoagulants, which can cause a wounded warrior to bleed out. Dialysis patients usually have to take anticoagulants so that their blood doesn’t clot inside the dialysis machine’s tubing.
For inspiration in approaching this challenge, Ingber and his colleagues looked to the human immune system—specifically, at a class of proteins in the blood that attach to potentially harmful microörganisms or toxins and mark them as targets for other immune cells. The group genetically engineered one such protein—known to bind to over 90 different pathogens, including bacteria, fungi, viruses, parasites, and toxins—so that it functions as a coating for magnetic nanobeads, giving them the ability to collect infectious agents in the bloodstream.
Following an injection of the beads, a patient’s blood is run through an external device that contains a system of microfluidic channels, the design of which is inspired by the spleen. In the device, which the inventors call a “spleen-on-a-chip,” contaminated blood flows through the channels alongside a saline solution. A magnetic-field gradient is then used to pull the nanobeads and their bound pathogens into that solution. Using this process, the group has already met DARPA’s goal of cleansing 1.25 liters of blood per hour, and Ingber says he believes they can achieve an even higher flow rate.
Lining the inner surface of the channels is a novel material called SLIPS (slippery liquid-infused porous surfaces), inspired by the Nepenthes pitcher plant and also developed at the Wyss Institute. SLIPS prevents proteins and platelets from sticking to the surface of the channels and activating clotting.
The potential of the technology does not end there. Since the system can remove and isolate pathogens so efficiently, it may provide an opportunity to identify the organism causing a patient’s infection without having to perform a blood culture, says Michael Super, a senior staff scientist at the Wyss Institute. This would reduce the amount of time needed to determine the appropriate antibiotic. The group is now working to build that capability into the device.