Enhanced bioadhesion of thiomer-based hydrogels by tissue surface pre-conditioning

Hydrogel constructs often exhibit insufficient soft-tissue adhesion, limiting retention and therapeutic function. Here, a tissue-interface engineering strategy enhances hydrogel adhesion through sequential dithiothreitol (DTT)-mediated thiol exposure and UV-anchored multi-arm PEG-acrylate priming, enabling improved coupling with cysteine-functionalized alginate (Alg-Cys). Alg-Cys is synthesized by carbodiimide coupling and characterized by FTIR, ¹H NMR, and Ellman's assay, showing ∼1200 µmol thiol groups per gram polymer. Cytocompatibility is confirmed using Caco2, C2C12, and HepG2 cells, and hemocompatibility is evaluated with human erythrocytes. Using ex vivo porcine tissues including small intestinal mucosa, skeletal muscle and liver, an optimized DTT treatment at 50 mM for 30 min increased accessible surface thiols in a tissue dependent manner, with mucosa showing the strongest response (∼2-fold). Subsequent PEG-acrylate priming further amplifies reactive surface functionalities, with 8-arm primers increasing immobilized acrylate groups up to 3.6-fold on mucosa, 3.4-fold on muscle, and 2.2-fold on liver. A 5% Alg-Cys formulation combined with 8-arm PEG-acrylate exhibits favorable rheological properties, shear-thinning behavior, and rapid structural recovery. Ex vivo adhesion testing demonstrates up to ∼2-fold enhancement in adhesion across all tissues. This sequential tissue activation strategy substantially strengthens hydrogel-tissue interfaces and provides a versatile approach to improving thiomer bioinks for in situ bioprinting and regenerative therapies.