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Several sensors are available to detect small molecules like glucose and electrolytes continuously, although designing sensors for proteins — which are larger and more complex — poses greater challenges. Scientists typically rely on DNA receptors that bind to proteins and extract them from biofluids to detect proteins in biological fluids. However, these receptors are too effective; their Velcro-like binding is so strong that even with passive regeneration, they can hold onto proteins for over 20 hours, preventing real-time measurement of protein fluctuations in the bloodstream. In response, scientists have now developed a novel implantable device capable of monitoring protein levels in real-time. In proof-of-concept studies, the sensors accurately and sensitively detected inflammation-related protein biomarkers in diabetic rats. This breakthrough could enable real-time management and prevention of both acute and chronic conditions by tracking critical proteins like cytokines in inflammation or protein markers in heart failure.

Inspired by the natural process of fruit falling from tree branches, researchers at Northwestern University (Evanston, IL, USA) designed a device made of DNA strands that bind to proteins, shake them off, and then capture more proteins. This innovation allows the device to track fluctuations in protein levels over time, such as changes in inflammatory markers. The nanoscale sensors resemble rows of bulbous pendulums, each consisting of a double-stranded DNA cord. One end of the DNA strand is attached to an electrode, while the other binds to a target protein. By applying an alternating electric field, the pendulum-like sensors swing back and forth, shedding proteins within a minute and capturing new ones.

After observing the device’s functionality in the lab, the team moved to test it in living animals. They created an implantable microdevice that housed the electrodes and sensors inside a microneedle just three human hairs thick. Similar to a continuous glucose monitor, this device sits on the skin with the microneedle inserted to sample body fluids. The researchers designed sensors to specifically target two cytokines, which are key inflammation markers, and implanted the device in diabetic rats. Given the strong link between diabetes and inflammation, which causes many diabetes-related complications, this setup allowed for real-time monitoring of cytokine levels. The sensors accurately detected fluctuations in cytokine levels when rats fasted or received insulin, with cytokine concentrations decreasing. When the rats were injected with a substance that stimulated their immune system, the cytokine levels surged.

The study, published in the journal Science, showed that the sensors were so sensitive that each time a rat received an insulin injection, the device detected a brief spike in inflammation at the needle insertion point. The sensor measurements also aligned with those from gold-standard laboratory methods for detecting proteins in bodily fluids, validating its effectiveness. Although the device was used to monitor inflammation in this study, the researchers plan to expand its applications to track other protein markers, such as B-type natriuretic peptide (BNP), a protein associated with heart failure. Currently, clinicians use BNP to diagnose and monitor heart failure, but there is no continuous real-time monitoring method for this protein marker.

“If you have heart failure, you might go to the doctor every three months,” said Northwestern’s Shana O. Kelley, who led the study. “But, as with most illnesses, symptoms occur between doctor’s visits. If a patient isn’t feeling well, it’s not immediately obvious that it’s due to heart failure. With a continuous monitor, when the patient doesn’t feel well, the doctor could pull up their data and check their BNP levels. Then, medications could be fine-tuned before symptoms worsen. We hope one day this technology will benefit many people, along the lines of what has happened with the positive impact of continuous glucose monitoring today. It could be the ultimate preventative measure.” 

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