Dual‐Gradient Silk‐Based Hydrogel for Spatially Targeted Delivery and Osteochondral Regeneration

Contemporary clinical interventions for cartilage injuries focus on symptom management through pharmaceuticals and surgical procedures. Recent research has aimed at developing innovative scaffolds with biochemical elements, yet challenges like inadequate targeted delivery and reduced load-bearing capacity hinder their adoption. Inspired by the spatial gradients of biophysical and biochemical cues in native osteochondral tissues, a silk-based hydrogel that facilitates spontaneous dual-gradient formation, including mechanical gradients and growth factor gradients, for tissue regeneration, is presented. Driven by an electrical field, the hydrogel transitions from stiff to soft along the anode-to-cathode direction, mimicking the anisotropic structure of natural tissues. Simultaneously, incorporated growth factors encapsulated by charged monomers migrate to the cathode region, creating another parallel gradient that enables their sustained release. This design maintains bioactivity and enhances programmable growth factor concentration in the defect environment. In a rabbit model with full-thickness osteochondral defects, the dual-gradient hydrogel demonstrates significant potential for promoting osteochondral regeneration, offering a promising tool for clinical translation.