Organic‐Inorganic Composite Hydrogel with Biomimetic Structural Gradient for Osteochondral Regeneration in Osteoarthritis

Abstract Osteochondral defect repair is a long‐standing clinical problem due to the difficulty in the reconstruction of complex graded structure from articular cartilage to subchondral bone. Replicating osteochondral‐analogous graded structure for defect regeneration is recognized as an ideal way although remains a challenge. Inspired by biomineralization, calcium phosphate ionic oligomers (CPOs) and hyaluronic acid (HA) is co‐assembled for a biomimetic osteochondral hydrogel (BiGOH) with both compositional and nano‐structural gradients through non‐classical crystallization. This spatial gradient ensured BiGOH with graded regulation of microenvironment cues: the chondrogenic anabolism is enhanced toward cartilage‐affinity region while the recruitment of macrophage and its pro‐inflammatory M1 to pro‐regenerative M2 transformation, and osteogenic differentiation is promoted toward subchondral bone‐affinity region. This anisotropic microenvironmental regulation significantly accelerated osteochondral regeneration in rat osteochondral defect model even under osteoarthritis condition that deteriorate the regenerative niche. Complete osteochondral tissue regeneration, which exhibits structural reconstruction of native osteochondral structures and seamless integration with surrounding tissues, can be realized within 8 weeks, which is the fastest one according to reported studies. This bioinspired mineralization from oligomer precursors offers a non‐classical crystallization pathway to manufacture biomimetic gradient architecture, and provides a feasible strategy for graded cellular regulation, pushing forward the understandings on osteochondral defect regeneration.