Diagnostics
Blood flows through a cartridge filled with hollow fibres that are coated with FcMBL, which removes pathogens and the toxins they release, in an effort to prevent the inflammatory cascade.
Military funding
The studies published by Ingber and Super caught the attention of Darpa, the research and development agency of the United States Department of Defense responsible for the development of emerging technologies for use by the military. “Companies had been developing portable dialysis units and the military had been deploying them in warzones,” says Ingber. “They were very interested in leveraging [our work] to develop sepsis therapy. That’s where a lot of our initial funding came from.” The original design using magnetic beads wasn’t viable for a device that had to be produced at scale, so Ingber and Super applied the FcMBL directly to a dialysis-like filter, and in doing so created a treatment for sepsis that’s been proven in studies to remove 120 clinically-relevant pathogens as well as the toxic products they release, known as Pathogen Associated Molecular Patterns (PAMPs), which trigger the inflammatory cascade that leads to sepsis.
“The holy grail will be direct capture and concentration from the blood, and identification using mass spectrometry, without the small amount of growth we had to do in the GOSH study.”
Michael Super
At this point, Ingber and Super had the capability to cleanse the blood of patients before the inflammatory cascade reached a tipping point and became full-blown sepsis, but they couldn’t identify the pathogen that caused that cascade. To do this, a diagnostic was required, but with the available methods taking at least a day, Ingber and Super had to find a way to decrease the time dramatically. Luckily, Darpa was on board with this idea too and in a subsequent project they funded the development of a diagnostic. “We had this great capture
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mechanism, but very poor identification,” says Super. “We can identify best with PCR if we know what we’re looking for, but the one that’s really good and fits in well with clinical practice is mass spectrometry, specifically MALDI-TOF mass spectrometry.” Matrix-assisted laser desorption-ionisation time-of-flight, or MALDI-TOF, is a type of mass spectrometry already used to help diagnose pathogens in systems like the Bruker Sepsityper kit, but the current method of centrifugation proved less accurate than combining the detection capability of the Sepsityper with FcMBL-coated beads. “It didn’t, for example, bind well to fungi or gram-positive [bacteria],” says Super. “It binds well to gram- negatives, whereas with the FcMBL technology, we were able to see all three.” Another important advantage was that the superior binding capability of FcMBL meant it could detect pathogens in lower quantities of blood.
This was a key part of the study, which was done in collaboration with Great Ormond Street Hospital for Children (GOSH). “It’s incredibly important in paediatrics because we find that you can’t get enough blood for the current blood cultures,” says Super.
Holy grail
The clinical value of identifying the pathogen(s) in the blood of a patient with sepsis isn’t hard to imagine; with a specific target, or potentially a group of targets, a physician can apply the correct antibiotic, antiviral, or antifungal medication, rather than taking the scattergun approach of broad-spectrum antibiotics. This is especially important, according to Super, given that cases of sepsis caused by fungal infection are on the rise. “In the time that I’ve been in this field, fungi have gone from the forgotten child to suddenly one of the major killers in ICUs,” he says.
Ingber and Super have achieved a great deal so far with FcMBL, with both the dialysis-like sepsis treatment device and the companion diagnostic licensed to BOA Biomedical, a Harvard spinout start-up company affiliated with technology investment and development company Miraki Innovation. But Super sees the next step as the most important for the clinic. “The holy grail will be direct capture and concentration from the blood, and identification using mass spectrometry, without the small amount of growth we had to do here [in the GOSH study],” he says. “If we could take the filter after the blood has been passed through it and extract the pathogens that were on it, then run those through a diagnostic, that to me is the next step. In fact, I feel we’re already there, we just haven’t done the study yet.”
Practical Patient Care /
www.practical-patient-care.com
Wyss Institute at Harvard University
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