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Point-of-care biosensor for rapid and accurate sepsis diagnosis

(Nanowerk Spotlight) Sepsis is the body's extreme response to an infection. It is life-threatening condition in which bacteria or fungi multiply in a patient's blood – often too fast for antibiotics to help. Without timely treatment, sepsis can rapidly cause tissue damage, organ failure, and death.
A critical unmet need in combating sepsis is the lack of accurate early biomarkers that can alert clinicians to a potential life-threatening situation and allow them to take preventative action.
In a new study published in ACS Nano ("Integrated Biosensor for Rapid and Point-of-Care Sepsis Diagnosis"), researchers report the development of a point-of-care platform for rapid sepsis detection, called IBS (integrated biosensor for sepsis).
Integrated biosensor for sepsis
Integrated biosensor for sepsis (IBS). Photo of the whole assay system. (Image: MGH Center for Systems Biology))
"In prior studies, our team had identified a previously unknown indicator to sepsis," Jouha Min, a postdoctoral researcher in Ralph Weissleder’s Lab at the Massachusetts General Hospital's Center for Systems Biology, and first author of the paper, tells Nanowerk. "Particularly, we have identified the inflammatory factor interleukin-3 (IL-3) as an independent predictor of septic shock and death." (Science, "Interleukin-3 amplifies acute inflammation and is a potential therapeutic target in sepsis").
Min recounts that translating this discovery into a clinically viable test, however, was difficult largely due to the lack of fast, easy-to-use, and sensitive platforms that could overcome the long assay time and complexity of the current gold standard protein quantification method called enzyme-linked immunosorbent assay (ELISA).
"Alternative approaches such as microfluidic chips have been demonstrated for rapid quantification, but their practicality in clinical settings is still limited due to the requirement of 1) sophisticated fluidic design and controls, and 2) large and/or expensive equipment for signal detection," he notes.
In this new work, the team aimed to validate that profiling IL-3 along with other host response cytokines in septic patients can identify diagnostic and prognostic signatures. Leveraging recent insights into the pathophysiology of sepsis with advances in engineering to design they set out to develop a novel point-of-care sepsis diagnosis platform.
The result is a fast, portable, wireless biosensor platform that can measure levels of a protein biomarker called cytokine interleukin-3 (IL-3) in the blood. This means that IBS could be a powerful assay system for sepsis diagnosis, which requires prompt treatment due to the acute nature of the disease.
This platform uses magnetic beads to directly and quickly extract target protein IL-3 from blood samples. The beads are decorated with antibodies and electron mediators, and through a series of reactions, generate an electrical current which provides an analytical readout of IL-3 levels.
"Technically, we implemented and optimized the integrated magneto-electrochemical biosensor platform, combining magnetic actuation and electrical detection," says Min. "This strategy has many practical advantages: 1) target protein markers can be enriched directly from whole blood; 2) the assay achieves high detection sensitivity through magnetic enrichment and enzymatic signal amplification; and 3), based on the electrical detection scheme, sensors can be readily miniaturized and expanded for parallel measurements."
In their study, the scientists applied IBS to detect IL-3 in clinical samples. They tested 62 blood samples (23 from septic patients and another 39 from non-septic) and achieved rapid (under one hour) and highly sensitive IL-3 detection in human blood samples.
The researchers' pilot clinical study supported the potential of IL-3 as an accurate surrogate biomarker of sepsis: 91.3% of patients with sepsis were correctly identified, and 82.4% of patients without sepsis were correctly diagnosed as not having the disease. In comparison, procalcitonin (PCT), another biomarker for sepsis, has been shown to have accuracies below 80%.
Because IBS is fast and requires a small blood sample, it can be readily adopted to track temporal changes of biomarkers. This capacity would aid in not only the timely diagnosis of acute septic shock, but also reliable prognostication assessment of the risk. Also, using a small sample would be especially advantageous for detection of sepsis in newborns/infants as blood samples from preterm infants are limited in volume.
The team points out that this technology is versatile to be extended to other sepsis markers and other infectious diseases.
Min notes that several aspects of the current study could be improved. "First, we envision creating a sepsis marker panel and expanding IBS for multiplexed detection. Robust characterization of host response for accurate diagnostics will ultimately require simultaneous assay of multiple markers. The initial candidate markers will include previously known targets such as IL-3, TNFα, IL-1β and IL-6. We will map clinical outcomes to the host response measured with the IBS. This will allow us to generate a quantitative prognostic algorithm."
"Second, sample preparation steps will have to be automated to realize a “sample-in and answer-out” system. We expect that the use of magnetic beads, thereby magnetic actuation, would facilitate replacing current manual operations with automation."
Min concludes that fully integrated, easy-to-use IBS will promote assay reproducibility and help collect large data set to test/validate/discover new biomarker(s) with clinical samples. With these developments, IBS would be a powerful clinical tool to enable early sepsis diagnosis and improve treatment outcomes.
By Michael is author of two books by the Royal Society of Chemistry: Nano-Society: Pushing the Boundaries of Technology and Nanotechnology: The Future is Tiny. Copyright © Nanowerk
 

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