On a Friday morning a few years ago, a childhood friend of mine walked into his doctor’s office, saying his hip hurt. The pain was pretty severe, and had been getting worse for several days.
By Saturday morning, he was in intensive care, fighting for his life against an overwhelming case of sepsis. He survived, but at a cost: he’s now a quadruple amputee.
It’s people like him—and the other million-plus Americans who develop sepsis every year—that Donald Ingber, MD, PhD, and his team had in mind while developing the biospleen, a device that filters sepsis-causing pathogens from the blood. Announced to the world in September, the biospleen grew out of the organs-on-chips technology that Ingber’s team at the Wyss Institute for Biomedically Inspired Engineering launched commercially this past summer.
Chipping away at sepsis
Nearly 20 years ago, Ingber—founding director of the Wyss Institute, Judah Folkman Professor of Vascular Biology at Harvard Medical School and a senior researcher in Boston Children’s Hospital’s Vascular Biology Program (VBP)—was collaborating with Harvard University chemistry professor George Whitesides, PhD, on technologies for microfluidic chips.
The Whitesides lab had worked out a way to create networks of microscopic channels filled with fluids, using methods first developed to make computer chips. But those microchannels, Ingber notes, had an interesting effect on fluid flow, one he thought could be useful for making a therapeutic device.
“At that small-size scale, you essentially have laminar flow,” he explains, referring to a phenomenon in fluid dynamics where two fluids flow side by side without mixing. “There’s no turbulence, no mixing. So if you engineer two inlets [into a chip] that join together into one larger vessel with two outlets, and put two different color dyes in, they don’t mix.”
Ingber’s lab thought they could harness that effect to develop a simple concept for cleansing inflammation-triggering pathogens and toxins from the blood of patients with sepsis. The idea was to mix the blood with magnetic nanoparticles coated with materials that would bind to the pathogens, and then pump the blood through a dialysis-like device alongside a neighboring flow of saline. Magnets would pull the pathogen-bound beads out of blood and into the saline, and the device would then return the cleansed blood to the patient.
In a 2009 Lab on a Chip paper, his lab reported proof-of-concept success, pulling more than 80 percent of Candida albicans fungi (a major sepsis pathogen) out of spiked, flowing human blood. He called the device a “spleen-on-a-chip,” because it mimicked the spleen’s ability to remove pathogens from blood.
A magnetic dust cloth for pathogens
The trick, though, was making the blood filter universal, so that it could remove any kind of pathogen. “When a patient comes to the intensive care unit with sepsis, you don’t know what the pathogen is,” Ingber says. “In fact, more than 50 percent of patients with fulminant sepsis have negative blood cultures; you never know what the pathogen is. You’re treating blindly.”
When he brought the technology over to the Wyss, Ingber found a solution: a protein we produce in our blood called mannose-binding lectin (MBL). Part of our innate immune system, MBL is a protein that latches on to a wide variety of sepsis-causing agents. “MBL can bind to more than 90 different gram-negative and -positive bacteria, fungi, viruses, parasites and different toxins like endotoxin,” Ingber explains.
In our bodies, MBL grabs hold of pathogens and guides them to the spleen for removal. To mimic this effect ex vivo, Ingber and Wyss scientists Joo Kang, PhD, and Michael Super, PhD, coated magnetic beads with a genetically modified form of MBL and combined them with an improved microfluidic device that more closely mimicked the spleen’s structure.
“When blood reaches the spleen, the flow slows down to a trickle in what are called sinusoids,” Ingber explains. “That’s where pathogens bind to MBL and macrophages pull bound MBL out of the circulation. The blood then returns to the venous system. So we developed a device with larger channels and sinusoid-like connections between channels.”
When the team tested the resulting biospleen against multiple pathogens in human blood and in a rat model of sepsis, the results were impressive. As they reported in Nature Medicine, after five hours of filtering, the biospleen removed 90 percent of pathogens and toxins from both spiked human blood and the rats’ bloodstreams. Survival among the treated animals was 90 percent, compared to 14 percent in controls.
To get the whole story, watch this video by Ingber and his team at the Wyss: