A Self‐Adaptive Biomimetic Periosteum Employing Nitric Oxide Release for Augmenting Angiogenesis in Bone Defect Regeneration

The periosteum plays a vital role in the regeneration of critical‐size bone defects and highly comminuted fractures, promoting the differentiation of osteoblasts, accelerating the reconstruction of the vascular network, and guiding bone tissue regeneration. However, the materials loaded with exogenous growth factors are limited by the release and activity of the elements. Therefore, the material structure must be carefully designed for the periosteal function. Here, a self‐adaptive biomimetic periosteum strategy is proposed, which is a novel interpenetrating double network hydrogel consisting of diselenide‐containing gelatin and calcium alginate (modified natural collagen and polysaccharide) to enhance the stability, anti‐swelling, and delayed degradation of the hydrogel. The diselenide bond continuously releases nitric oxide (NO) by metabolizing endogenous nitrosated thiols (RSNO), activates the nitric oxide‐cycle guanosine monophosphate (NO‐cGMP) signal pathway, coordinates the coupling effect of angiogenesis and osteogenesis, and accelerates the repair of bone defects. This self‐adaptive biomimetic periosteum with the interpenetrating double network structure formed by the diselenide‐containing gelatin and calcium alginate has been proven to be safe and effective in repairing critical‐size bone defects and is expected to provide a promising strategy for solving clinical problems. The double network hydrogel has the ability of rapid gelation and can balance the mechanical strength and toughness. The diselenide bond structure in the artificial periosteum can catalyze the endogenous S‐nitrosated thiols (RSNO) to produce nitric oxide (NO), which is conducive to adhesion, proliferation, osteoblastic differentiation, and angiogenesis, thus inducing the healing of critical‐size bone defects.