Harvard’s Wyss Institute improves its sepsis therapeutic device
Date: Aug 20, 2015
The Institute's blood-cleansing device, enabled by a genetically engineered pathogen-capturing protein, has been simplified to accelerate its clinical translation
(BOSTON) —Last year, a Wyss Institute team of scientists described the development of a new device to treat sepsis that works by mimicking our spleen. It cleanses pathogens and toxins from blood circulating through a dialysis-like circuit. Now, the Wyss Institute team has developed an improved device that synergizes with conventional antibiotic therapies and that has been streamlined to better position it for near-term translation to the clinic. The improved design is described in the October volume 67 of Biomaterials.
This video explains how sepsis induced by an overload of blood pathogens can be treated with the Wyss Institute’s improved pathogen-extracting, spleen-mimicking device. Blood is flown through a cartridge filled with hollow fibers that are coated with a genetically engineered blood protein inspired by a naturally occurring human molecule called Mannose Binding Lectin (MBL). MBL is activating our innate immune system when bound to toxic invaders, marking them for capture by immune cells in the spleen. Credit: Wyss Institute at Harvard University
Sepsis is a common and frequently fatal medical complication that can occur when a person's body attempts to fight off serious infection. Resulting widespread inflammation can cause organs to shut down, blood pressure to drop, and the heart to weaken. This can lead to septic shock, and more than 30 percent of septic patients in the United States eventually die. In most cases, the pathogen responsible for triggering the septic condition is never pinpointed, so clinicians blindly prescribe an antibiotic course in a blanket attempt to stave off infectious bacteria and halt the body's dangerous inflammatory response.
But sepsis can be caused by a wide-ranging variety of pathogens that are not susceptible to antibiotics, including viruses, fungi and parasites. What's more, even when antibiotics are effective at killing invading bacteria, the dead pathogens fragment and release toxins into the patient's bloodstream.
"The inflammatory cascade that leads to sepsis is triggered by pathogens, and specifically by the toxins they release," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who leads the Wyss team developing the device and is the Judah Folkman Professor of Vascular Biology at Boston Children's Hospital and Harvard Medical School and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Science. "Thus, the most effective strategy is to treat with the best antibiotics you can muster, while also removing the toxins and remaining pathogens from the patient's blood as quickly as possible."
The Wyss team's blood-cleansing approach can be administered quickly, even without identifying the infectious agent. This is because it uses the Wyss Institute's proprietary pathogen-capturing agent, FcMBL, that binds all types of live and dead infectious microbes, including bacteria, fungi, viruses, as well as toxins they release. FcMBL is a genetically engineered blood protein inspired by a naturally-occurring human molecule called Mannose Binding Lectin (MBL), which is found in the innate immune system and binds to toxic invaders, marking them for capture by immune cells in the spleen.
The original device concept was similar to how a dialysis machine works: infected blood in an animal, or potentially one day in a patient, is flowed from one vein through catheters to the device where FcMBL-coated magnetic beads are added to the blood, and then the bead-bound pathogens are extracted from the circulating blood by magnets within the device before the cleansed blood is returned to the body through another vein.
The blood-cleansing device connected to a dialysis-like circuit is harboring a dense pack of parallel running hollow fibers whose inner surfaces are covered with the Wyss Institute’s genetically engineered Mannose-binding lectin (MBL) protein, called FcMBL. When septic blood is streamed through the device, FcMBL effectively extracts viruses, fungi and parasites as well as toxins and dead pathogen fragments released into the bloodstream by antibiotic killing. Credit: Wyss Institute at Harvard University
The new and improved device removes the complexity, regulatory challenges and cost associated with the magnetic beads and microfluidic architecture of its predecessor, but it retains the ability of the FcMBL protein to bind to all different kinds of live or dead pathogens and toxins. The optimized system uses hollow fiber filters found in already-FDA-approved dialysis cartridges whose inner walls are coated with FcMBL protein to remove pathogens from circulating blood. In animal studies, treatment with this new pathogen-extracting device reduced the number of E. coli, Staphylococcus aureus and endotoxins circulating in the bloodstream by more than 99 percent.
"Using the device, alone or alongside antibiotics, we can quickly bring blood back to normal conditions, curtailing an inflammatory response rather than exacerbating it," said the paper's first author Tohid Fatanat Didar, Ph.D., Postdoctoral Fellow at the Wyss Institute and Research Fellow at Boston Children's Hospital. "If all goes well, physicians will someday be able to use the device in tandem with standard antibiotic treatments to deliver a one-two punch to pathogens, synergistically killing and cleansing all live and dead invaders from the bloodstream."
With the new improved blood-cleansing therapeutic device proving extremely effective in small animal studies, the Wyss team is planning to move to large animal studies as a next step to demonstrate the proof-of-concept that is required before it could advance to human clinical trials.
"Seeing our system work in animal models gives us confidence that this could work in humans, because we are successfully treating animals infected with human pathogens," said Wyss Senior Staff Scientist Michael Super, Ph.D., who works on the Institute's Advanced Technology Team and is also an author on the new study.
"Since the development of earlier prototypes of the device, we've applied the Wyss model of de-risking the technology to prime it for commercialization," said Ingber. "Our goal is to see this move out of the lab and into hospitals as well as onto the battlefield, where it can save lives within years rather than decades."
This work was supported by the Defense Advanced Research Projects Agency and the Wyss Institute for Biologically Inspired Engineering at Harvard University.
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The Wyss Institute for Biologically Inspired Engineering at Harvard University (http://wyss.harvard.edu) uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new start–ups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, and Charité – Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology.