Covalently Functionalized Click Alginate Cryogels Enable Non-Invasive Near-Infrared Sensing of Gastric pH

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 stable in acid and against proteases, and excess norbornene from crosslinking becomes 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, with extra-gastric organ and plasma fluorescence comparable to untreated controls. Ex vivo photoacoustic imaging shows pH-dependent contrast, pointing toward deeper-tissue detection. These results establish covalently functionalized cryogels as a non-invasive sensing platform for hostile physiological environments.