How does a shaking sensor provide real-time cytokine monitoring?
Cytokines in Inflammation
Continuous monitoring of inflammatory markers is essential for the early detection, accurate assessment, and effective management of both acute and chronic diseases. In acute conditions such as sepsis, pneumonia, and acute respiratory distress syndrome (ARDS), inflammatory markers like C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and cytokines including interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) rise rapidly in response to infection or tissue injury.
In-Vivo Cytokine Monitoring
Regular monitoring of these markers helps clinicians assess disease severity, guide antibiotic therapy, and evaluate treatment response in real time. In chronic diseases such as rheumatoid arthritis, type 2 diabetes, inflammatory bowel disease, systemic lupus erythematosus, and cardiovascular disorders, persistent low-grade inflammation contributes to progressive tissue damage and complications. Continuous monitoring of cytokine profiles and other inflammatory markers in these cases allows for early identification of flare-ups, adjustment of therapeutic regimens, and prevention of long-term organ damage. Moreover, ongoing assessment facilitates personalized treatment strategies by tailoring interventions according to an individual’s inflammatory status, ultimately improving clinical outcomes and quality of life.
Clinicians and researchers have long lacked the ability to monitor cytokine levels continuously within living organisms. Measurements rely on blood samples being taken and laboratory assays that provide only static “snapshots” rather than real-time data.
A team led by Shana O. Kelley, PhD, at Northwestern University and the Chan Zuckerberg Biohub Chicago unveiled an implantable “active-reset” biosensor capable of continuous, real-time cytokine monitoring in living animals.
The Challenge
Cytokines act as early-warning signals of inflammation and immune activation. Elevated IL-6 and TNF-α concentrations correlate with disease activity and prognosis in disorders such as rheumatoid arthritis, type 2 diabetes, and heart failure.
Affinity-based biosensors that use antibodies or aptamers can detect cytokines but suffer from slow dissociation kinetics (half-lives up to ~20 hours), meaning that once a protein binds, it remains attached long after physiological levels fall. This kinetic bottleneck prevents real-time monitoring of decreases in concentration.
The “Active Reset” Concept
The Northwestern–CZ Biohub team tackled this problem by actively resetting the sensor surface rather than waiting for natural dissociation.
Each sensing unit consists of a double-stranded DNA tether anchored to a gold electrode, terminating in an aptamer receptor that binds the target protein. When an alternating electric potential (~0.3 V at 95 Hz) is applied, the tether oscillates generating drag and inertial forces that rapidly dislodge bound cytokines.
The sensor resets to its unbound state within one minute, a dramatic improvement over the 20-hour passive dissociation time typical of protein–aptamer complexes.
Molecular dynamics simulations confirmed that oscillations reduce hydrogen bonding between the aptamer and the cytokine, increase solvent exposure, and destabilize the complex — the physical mechanism behind this “shaking off” process.
Microneedle Device for Interstitial Fluid Sampling
The researchers integrated these active-reset sensors into a microneedle designed to penetrate the skin and access interstitial fluid (ISF), a biofluid that mirrors plasma cytokine composition.
Computational fluid dynamics modelling showed that the microneedle fills with ISF in
Biocompatibility was carefully validated:
- No meaningful differences in immune-cell infiltration or histological abnormalities were found between tissues from control rats and those implanted with microdevices.
- A 66-gene inflammatory pathway panel showed no significant changes in gene expression pre- and post-oscillation.
- The device exhibited minimal cytotoxicity and maintained mechanical integrity for skin penetration (Young’s modulus ≈ 3.1 GPa).
In Vivo Cytokine Monitoring in Diabetic Rats
The team validated the technology in diabetic rat models, where chronic inflammation contributes to vascular injury and metabolic dysfunction.
Sensors designed for IL-6 and TNF-α detection (using picomolar-affinity aptamers) continuously measured cytokine levels over six hours within the range of 10–500 pg/mL.
Key results:
- During fasting, IL-6 levels dropped from ~520 to ~190 pg/mL, consistent with inflammation reduction via autophagy and metabolic regulation.
- Insulin injection caused a transient cytokine spike, followed by normalization, likely reflecting localized tissue response.
- Lipopolysaccharide (LPS) administration triggered a sharp IL-6 and TNF-α rise, demonstrating the sensor’s responsiveness to immune activation.
- Continuous readings correlated strongly with ELISA-based serum and ISF measurements (validated via Bland–Altman analysis).
The device performed stably for >350 minutes without biofouling or drift, a milestone for in vivo protein sensing.
IMAGE Atypical erythema three days after removal of a Borrelia-positive tick from skin at the hollow of the knee CREDIT: Turelio
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