Gelatin-Based Ingestible Impedance Sensor for Diagnosing Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is an allergen-induced esophageal inflammatory condition that affects over 200,000 patients in the United States, causing symptoms such as dysphagia, chest pain, and heart burn. With a lack of effective treatment options, early diagnosis and allergen identification is key in managing EoE. Current diagnostic protocols involve frequent endoscopies and tissue biopsies, creating an inconvenient and painful experience for patients. Research has shown that electrical impedance can be used to diagnose EoE because of intercellular dilation. Here, we design, fabricate, and test a gelatin-based ingestible impedance sensing capsule using both <i>in vitro</i> and <i>ex vivo</i> test beds.<br/>Impedance sensing capsules were fabricated by integrating microfabricated thin-film electrodes with soft gelatin-based structural materials via a custom aqueous-phase transfer printing method. Through controlling the addition of a non-volatile solvent glycerol (50% v/v) and cross-linking agent genipin (10% crosslinking), the mechanical properties of the gelatin substrate were optimized (E ~25kPa, ε_max ~200%). The transferred devices on a 0.5 mm gelatin substrate demonstrate a low bending stiffness of 1.5×10^-8 Nm², allowing for the structures to be easily wrapped around a cylinder of 1 cm to form a capsule.<br/>The microfabricated sensors were first tested using a synthetic electrochemical tissue phantom comprising varying volume fractions of 20μm dielectric polystyrene (PS) microparticles dispersed in ionic agarose hydrogels to mimic changes in intercellular spacing. The impedance spectra show that composites with higher PS volume fractions display higher impedances and effective solution resistance values. Furthermore, normalized experimental impedance spectra show strong agreement with predicted spectra calculated using a Poisson-Nernst-Planck model of the composite system.<br/>An <i>ex vivo</i> disease model was generated by treating porcine esophageal explants in 0.1 M HCl. Histology was performed to show that there is damage induced to the epithelial layer, causing an increased intercellular spacing. Microfabricated sensors interfaced with planar tissue section show that they are capable of distinguishing between the healthy and damaged tissues, with an over three-fold difference between the impedance of healthy and diseased tissue at 10kHz (Z_healthy = 10kΩ, Z_diseased= 3kΩ). Following this, 8-channel multiplexed impedance measurements were performed using the gelatin-based sensing capsules linearly translated through a porcine esophagus to obtain impedance heat maps. It is observed that the electrodes have sufficient contact with the epithelial tissue, with a significant increase in impedance on exit from the esophagus (Z_{in eso} = 15kΩ, Z_{out eso} = 200kΩ; @ 10kHz). Additionally, the sensors provide accurate impedance measurements through healthy and diseased esophagi at translation velocities similar to the rate of swallowing (v = 8 cm/s).<br/>In conclusion, ingestible impedance sensors are a promising non-invasive and reliable platform to diagnose eosinophilic esophagitis. The presented transfer printing method is a versatile technique that can be useful in fabricating soft, hydrogel devices for a wide range of soft bioelectronic applications. Lastly, the <i>in vitro</i> synthetic model is a promising testbed for conditions that result in the impeded barrier function of epithelial tissues.