Tannic acid-assisted mechanical training transforms natural hydrogels into robust and bioactive membranes for guided...

Guided bone regeneration (GBR) membranes are widely used for the treatment of bone defects. Natural hydrogels are promising candidates for GBR membranes owing to their excellent bioactivity and controllable degradability, but their clinical translation is restricted by inherent mechanical weakness. Inspired by tendon-strengthening mechanisms in athletes, we propose a tannic acid (TA)-assisted wet-stretching (TAWS) strategy to transform gelatin methacryloyl (GelMA) hydrogels into mechanically robust GBR membranes. During stretching, GelMA chains are directionally aligned while TA establishes multivalent hydrogen bonds between adjacent fibers, synergistically reinforcing the network. The resulting TA-trained (GHT) membranes achieved a 22.16-fold increase in Young's modulus and a 12.31-fold enhancement in toughness. In parallel, TAWS markedly slowed degradation kinetics and enhanced physiological stability, enabling GHT membranes to retain ∼80 % of their initial mass after 28 days in SBF. Beyond reinforcement, TA imparted potent ROS-scavenging and immunomodulatory activity. In vitro, GHT membranes enhanced stem cell survival, proliferation, and osteogenic differentiation under oxidative stress. In a mandibular defect model under elevated oxidative and inflammatory challenge, GHT reduced ROS levels (DHE fluorescence) to 53.76 % of the untreated ROS-upregulated group and increased bone volume fraction (BV/TV) by approximately 2.68-fold at 4 weeks and 2.21-fold at 8 weeks, outperforming the Bio-Gide® membrane. Collectively, TAWS provides a scalable platform to engineer multifunctional hydrogel membranes that integrate mechanics, stability, and regenerative performance for advanced GBR.