Development of a novel potential difference probe with bedside validation simulator for potential difference testing

Cystic fibrosis (CF) is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, leading to abnormal anion transport and consequent airway dehydration and hyper-viscous mucus. Potential difference (PD) testing measures voltage across the epithelium and can be a sensitive marker for changes in ion transport reflective of CFTR activity. By the conventional method, agar gel salt-bridge-based probes in combination with calomel electrodes have been used to measure transepithelial PD across the respiratory mucosa, allowing discrimination between healthy controls and CF. This method is known to be cumbersome and subject to errors due to discontinuity in salt bridges as a result of entrained air that are difficult to detect and a lack of real time visual guidance for probe placement, adversely affecting quality control and data analysis. These limitations are particularly relevant to endobronchial PD, where visualization is less precise, and the chance of electrical discontinuity with extended salt bridges is greater. We developed a novel portable probe system with onboard silver-silver chloride electrodes, integrated gas removal to extract gas bubbles, and optical coherence tomography-mediated visual guidance to provide a platform for improved accuracy and sensitivity of CFTR functional testing that can be adapted for endobronchial PD testing. We also developed a bedside electrocell simulator for the validation of probe performance, ensuring real-time external validation and use of probes that exhibit optimal performance characteristics before human measurements. In a pilot nasal PD study in CF subjects and non-CF controls (<i>n</i> = 10), measurements with the new probe were feasible with discrimination between disease groups. Bland-Altman suggested limited agreement (mean difference: -2.44, SD 4.79; 95% limits of agreement -11.84 to 6.95), but the Deming regression demonstrated a consistent linear relationship despite proportional bias (<i>b</i> = 1.21, <i>P</i> < 0.001) and the Somers' D indicated moderate concordance in rank ordering (0.56; 95% CI: -0.24 to 0.90). These results establish proof of principle of the new device and support the need for further validation in a larger sample.<b>NEW & NOTEWORTHY</b> Cystic fibrosis (CF) impairs CFTR protein function, disrupting ion transport and airway hydration. Traditional potential difference (PD) testing uses salt-bridge probes and calomel electrodes, but is error-prone due to air bubbles and poor visual guidance, especially in endobronchial applications. A novel probe with integrated silver-silver chloride electrodes, gas removal, and OCT guidance improves accuracy and usability. Validation through benchtop and preliminary human nasal testing shows 55% concordance with conventional methods, supporting its clinical potential.