Sequential Therapy for Osteosarcoma and Bone Regeneration via Chemodynamic Effect and Cuproptosis Using a 3D‐Printed Scaffold with TME‐Responsive Hydrogel

Post-surgical recurrence and extensive bone defects pose significant challenges during osteosarcoma treatment. These issues can be addressed using a novel strategy that promotes bone repair after removing residual tumors. Therefore, a 3D-printed porous polylactic acid (PLA) scaffold (PH-GBS@CCP) filled with hydrogel and surface-modified with nano-hydroxyapatite (nHA) is designed. The hydrogel, composed of gelatin modified with methacrylic anhydride (GelMA), sodium alginate (SA), and borax, contains Cu-Cys-PEG nanoparticles (CCP) modified with cRGD_fk-PEG_2K-DSPE. It is injected into the PLA scaffold and crosslinked under UV. This hydrogel acts as a buffer medium between scaffold and bone, reducing cell abrasion, and as a carrier for the responsive release of tumor-targeting CCP. The scaffold provides the support and microenvironment required for bone repair. In early treatment, the acidic tumor microenvironment promotes hydrogel disintegration and CCP release, depleting glutathione and converting Cu²⁺ to Cu⁺ for the Fenton-like reaction. This generates reactive oxygen species, strengthening the proptosis effect, and killing the tumor. In later treatment, after tumor elimination, normalized pH and slow CCP release, along with scaffold nHA, promote osteogenic differentiation, providing a sustained osteogenic effect. Overall, the multifunctional composite scaffold achieved the sequential management of post-surgical osteosarcoma through early tumor-killing and later osteogenic effects.