Continuous mechanical-gradient hydrogel with on-demand distributed Mn2+/Mg-doped hydroxyapatite@Fe3O4 for functional osteochondral regeneration

Traditional layered gradient scaffolds are susceptible to delamination owing to abrupt stress alterations, thereby rendering them inefficacious for the integrated repair of osteochondral defects. This study proposed a novel hydrogel possessing continuous magnetic-mechanical and multiple functional metal elements gradients. The establishment of these gradients within the hydrogel was accomplished by first applying a magnetic field to FMHM particles (Fe 3 O 4 deposited with Mg-doped hydroxyapatite (MgHA@Fe 3 O 4 ) and grafted with γ-(methacryloyloxy) propyl trimethoxysilane) dispersed in poly (ethylene glycol) diacrylate/sodium alginate solution to create a gradient, followed by thermal polymerization to achieve the magnetic and mechanical gradients. Subsequently secondary crosslinking with Mn 2+ realized the gradient distribution of Mn 2+ which was reverse to the gradient of MgHA@Fe 3 O 4 . The on-demand gradient distributions of Mn 2+ and MgHA@Fe 3 O 4 enhanced cartilage and osteogenic differentiation of bone marrow-derived mesenchymal stem cells, respectively. The continuous gradient hydrogel attained remarkable repair effects on full-thickness osteochondral defects in rat knee joints. Its capacity to foster the growth of both cartilage and subchondral bone may be associated with the fact that the mechanical gradient modulated the gradient nuclear localization and expression of the mechanosensitive factor Yes-associated protein 1. With stiffness and magnetism gradients, along with the on-demand synergistic impacts of multi-gradient metal elements Mn-Fe/Mg/Ca, this hydrogel presents a prospective option for the regeneration of tissues/interface tissues exhibiting physiological gradients. • Hydrogel with dual continuous magnetic and mechanical gradients was proposed and constructed. • Reverse gradients of Mn 2+ and MgHA@Fe 3 O 4 of hydrogel promoted chondrogenic and osteogenic differentiations of BMSCs. • The differentiation of BMSCs on gradient hydrogel may be related to the nuclear localization and expression of YAP1. • Effects of uniform, hierarchical, and continuous gradient hydrogels in osteochondral repair were systematically compared.