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Biospleen Helps Clean Blood to Prevent Sepsis

When a patient has sepsis, things can go downhill fast. A life-threatening condition in which bacteria or fungi multiply in a patient’s blood — sepsis is often too fast for antibiotics to help. But that’s all about to change with the introduction of a new device — inspired by the human spleen — that may radically transform the way doctors treat sepsis.

“Even with the best current treatments, sepsis patients are dying in intensive care units at least 30 percent of the time,” said Mike Super, Ph.D. “We need a new approach.”

To put things into perspective sepsis kills at least eight million people worldwide each year and it’s the leading cause of hospital deaths.

The Spleen-on-a-chip, developed at the Wyss Institute, will be used to treat bloodstream infections that are the leading cause of death in critically ill patients and soldiers injured in combat. Image credit goes to: Wyss Institute

The Spleen-on-a-chip, developed at the Wyss Institute, will be used to treat bloodstream infections that are the leading cause of death in critically ill patients and soldiers injured in combat. Image credit goes to: Wyss Institute

The device, called a “biospleen,” exceeded the team’s expectations with its ability to cleanse human blood tested in the laboratory and increase survival in animals with infected blood. In a matter of hours, it can filter live and dead pathogens from the blood, as well as dangerous toxins that are released from the pathogens.

Sepsis occurs when a patient’s immune system overreacts to a bloodstream infection, triggering a chain reaction that can cause inflammation, blood clotting, organ damage, and death. The process is vaguely similar to what happens when someone contracts ebola, the body tries to overcompensate and unfortunately it does more harm than good.

Sepsis can arise from a variety of infections, including appendicitis, urinary tract infections, skin or lung infections, as well as contaminated IV lines, surgical sites, and catheters. Identifying the specific pathogen responsible for sepsis can take several days, and in most patients the causative agent is never identified.

If doctors are unable to pinpoint which types of bacteria or fungi are causing the infection, they treat sepsis patients empirically with broad-spectrum antibiotics – but these often fail in many cases and in most cases they can have devastating side-effects. The sepsis treatment challenge continues to grow more complex as the prevalence of drug-resistant bacteria increases while the development of new antibiotics lags.

“This is setting the stage for a perfect storm,” said Super.

The group set out with the team to build a fluidic device that works outside the body like a dialysis machine, and removes living and dead microbes of all varieties — as well as toxins. They modeled it after the microarchitecture of the human spleen, an organ that removes pathogens and dead cells from the blood through a series of tiny interwoven blood channels.

This image demonstrates the effectiveness of the genetically engineered protein-coated magnetic beads binding to pathogens. Here, the magnetic beads (128 nm) are bound to two pathogens (E. coli on the left and S. aureus on the right) Image credit goes to: Harvard's Wyss Institute

This image demonstrates the effectiveness of the genetically engineered protein-coated magnetic beads binding to pathogens. Here, the magnetic beads (128 nm) are bound to two pathogens (E. coli on the left and S. aureus on the right) Image credit goes to: Harvard’s Wyss Institute

The biospleen is a microfluidic device that consists of two adjacent hollow channels that are connected to each other by a series of slits: one channel contains flowing blood, and the other has a saline solution that collects and removes the pathogens that travel through the slits.

The key to the success of the device are tiny nanometer-sized magnetic beads that are coated with a genetically engineered version of a natural immune system protein called mannose binding lectin (MBL).

In its innate state, MBL has a branch-like “head” and a stick-like “tail.” In the body, the head binds to specific sugars on the surfaces of all sorts of bacteria, fungi, viruses, protozoa and toxins, and the tail cues the immune system to destroy them. However, sometimes other immune system proteins bind to the MBL tail and activate clotting and organ damage – so scientists used genetic engineering tools to lop off the tail and graft on a similar one from an antibody protein that does not cause these problems.

The team then attached the hybrid proteins to magnetic beads 128 nanometers in diameter approximately one-five hundredths the width of a human hair to create novel beads that could be added to blood of an infected patient to bind to the pathogens and toxins without having to first identify the type of infectious agent. The sepsis device then has a magnet that pulls the pathogen-coated magnetic beads through the channels to cleanse the blood flowing through the device, which is then returned to the patient.

The researchers first tested their blood-cleaning system using human blood in the laboratory that was spiked with pathogens. They were able to filter blood much faster than ever before, and the magnets efficiently pulled the beads – coated with the pathogens – out of the blood. In fact, more than 90 percent of key sepsis pathogens were bound and removed when the blood flowed through a single device at a rate of about a half to one liter per hour, and many devices can be linked together to obtain levels required for human blood cleansing at dialysis-like rates.

Next they tested the device using rats that were infected with E. coli, S. aureus, and toxins – mimicking many of the bloodstream infections that human sepsis patients experience. Quite similar to the tests on human blood, after just five hours of filtering, about 90 percent of the bacteria and toxin were removed from the rats’ bloodstream.

“We didn’t have to kill the pathogens. We just captured and removed them,” Super said. What’s more, 90 percent of the treated animals survived compared to 14 percent of the controls — and sure enough, thanks to the team’s modified MBL, the immune system had not overreacted.

“Sepsis is a major medical threat, which is increasing because of antibiotic resistance. We’re excited by the biospleen because it potentially provides a way to treat patients quickly without having to wait days to identify the source of infection, and it works equally well with antibiotic-resistant organisms,” said Ingber.

“We hope to move this towards human testing to advancing to large animal studies as quickly as possible.”

Of course even with trying to push for quicker trials the biospeen will probably still be a few years out. FDA regulations are pretty strict here in the US, which isn’t always a bad thing. Still, with all the new medical advancements that are coming soon, it’s exciting to watch them work their way to mainstream medical use.

Sources
Kang JH, Super M, Yung CW, Cooper RM, Domansky K, Graveline AR, Mammoto T, Berthet JB, Tobin H, Cartwright MJ, Watters AL, Rottman M, Waterhouse A, Mammoto A, Gamini N, Rodas MJ, Kole A, Jiang A, Valentin TM, Diaz A, Takahashi K, & Ingber DE (2014). An extracorporeal blood-cleansing device for sepsis therapy. Nature medicine PMID: 25216635

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