Abstract
Abstract
Gastric acidity shapes mucosal injury in reflux disease, peptic ulcer, and gastritis, yet is almost never measured. Acid-suppressive therapy, taken by approximately 40% of elderly adults, is therefore titrated on symptoms alone. A gastric sensor must hold onto its reporter in a highly acidic protease-rich environment, conditions that destabilize ionically crosslinked hydrogels and leach physically entrapped dyes. Click alginates, established in biomechanics and drug delivery but not as sensors, meet this requirement with a single chemistry: bioorthogonal tetrazine-norbornene crosslinks are inert to acid and proteases, and excess norbornene from crosslinking become the anchoring site for the pH-sensitive reporter, so network and reporter are installed by the same mechanism. Cryogelation adds macroporosity for rapid gastric fluid influx. A screen identifies IRDye 680RD as the only near-infrared dye responsive across the targeted pH 2-5. Dye release stays below 1.5% in simulated gastric and intestinal fluids, and the pH response remains active after nine months of storage. In rats, the orally administered NIR fluorescent cryogel resolves pH 2.0 from pH 5.0 transabdominally, and discriminates esomeprazole-from saline-treated animals, without plasma fluorescence. Photoacoustic imaging points toward detection at translationally relevant depths, establishing covalently functionalized cryogels as a general sensing platform for hostile physiological environments.