Calcium ions are central to how olfactory receptor neurons detect and adapt to odors. Normally, calcium helps regulate odor signal strength and resets neurons for the next stimulus. However, excessive calcium in the nasal cavity can disrupt this balance, dampening olfactory signals and contributing to anosmia (complete smell loss) or hyposmia (partial smell loss).
Despite prior research highlighting this association between calcium homeostasis and poor olfactory signaling, there is currently no validated method for measuring calcium directly in nasal secretions, a gap this study seeks to fill.
The Study
The sensor design is simple but effective. A strip of paper is coated with conductive ink made from multi-walled carbon nanotubes (MWCNTs) and carbon dots synthesized from guava fruit. The combination of these nanostructures enhances electrical conductivity while maintaining biocompatibility.
A calcium-selective ionophore known as ETH 1001 is central to its workings; ETH 1001 binds specifically to calcium ions in the sample, which can then be detected potentiometrically. A reference electrode made with silver chloride and potassium chloride ensures accurate readings.
The paper strip is coated to a precise thickness of 50 microns, equivalent to the thickness of a human hair, chosen after comparative tests with thinner and thicker layers. Tests found this thickness provided an optimized balance of sensitivity, stability, and ease of fabrication. ETH 1001 was tested at concentrations of 1 %, 2 %, 4 %, and 6 %, with 4 % found to offer the best balance of response and stability.
When using the sensor in tests, the team first treated nasal mucus samples with a standardized method, adding buffer, removing protein, and centrifuging. These steps are required for reliable, accurate results without interference from biological materials.
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The research team found that the sensor responds to calcium concentrations ranging from 10-1 to 10-1 M, covering physiological and pathological levels. It demonstrated a near-Nernstian slope of 29.14 mV per decade, a strong indicator of signal accuracy. Its limit of detection was 7.5 × 10-8 M, significantly better than previously reported devices.
It remains stable over six months, with minimal drift in signal, and performs reliably across a pH range of 2 to 9, reflecting the variability found in real nasal samples. The response time of around 20 seconds is acceptable for clinical settings, though slightly slower than some alternatives. This moderate response time reflects a trade-off between sensitivity and speed inherent in the sensor’s paper-based architecture.
Selectivity tests confirmed that common nasal electrolytes such as sodium, potassium, magnesium, and zinc do not interfere with calcium detection, thanks to the high specificity of the ionophore ETH 1001.
Clinical Testing
After tests in the lab, the sensor was clinically assessed. Samples from 166 participants were used, including 100 patients with anosmia (loss of smell) and 66 healthy controls. Olfactory function was assessed using the established Sniffin’ Sticks test.
On average, calcium levels in patients with smell loss were significantly higher (7.30 × 10-2 M) than in healthy individuals (1.84 × 10-2 M). This trend held across different causes of anosmia, including post-COVID-19, trauma, sinonasal disease, and idiopathic cases, although subgroup comparisons did not all reach statistical significance.
Nonetheless, all anosmia subgroups showed elevated calcium concentrations relative to controls, supporting the broader link between disrupted calcium signaling and olfactory impairment.
A Future in Point-of-Care Diagnostics
The sensor meets several World Health Organization criteria for ideal diagnostic tools: affordability, specificity, ease of use, and portability. Though limitations remain, in particular the moderately slow response time and potential variability due to coating uniformity and ionophore distribution, the study marks a step forward in accessible diagnostics for sensory disorders.
Future development could focus on optimizing membrane consistency, enhancing fluid flow through microfluidic integration, or exploring alternative ionophores to further reduce response time and improve reproducibility.
Journal Reference
Imam M.S., et al. (2025). Nanoparticle-modified paper-based analytical sensor for calcium determination in human nasal secretions and its association with olfactory dysfunction. Scientific Reports 15, 35574. DOI: 10.1038/s41598-025-23104-w, https://www.nature.com/articles/s41598-025-23104-w