3D-printed scaffold with biomimetic gradient structure for promoting bone regeneration through inhibiting inflammation and facilitating in-situ biomineralization

Critical-sized bone defects caused by trauma, congenital malformation, or tumor resection remain a major challenge around the world. Current bone tissue-engineering scaffolds are partially confined by inadequate scaffold architecture design that mismatches with natural bone tissue, which affect normal biological functions like inflammation modulation and biomineralization, thus impairing bone regeneration process. Herein, a biomimetic 3D-printed BMGP scaffold composed of polydopamine (PDA)-polylactide (PLA) scaffold and black phosphorus (BP) nanosheets/manganese carbonyl (MnCO) nanosheets/gelatin methacryloyl hydrogel (named as BMG hydrogel) was developed for augmenting bone regeneration via strengthening anti-inflammatory effect and promoting in-situ biomineralization process. Through infilling the BMG hydrogel into the gradient-porous PDA-PLA scaffold, the obtained BMGP scaffold successfully mimicked cancellous and compact bone structure and extracellular matrix component in natural bone tissue. Upon being implanted into the critical-sized bone defect, a Fenton-like reaction between the MnCO nanosheet and endogenous hydrogen peroxide effectively induced carbon monoxide release, thereby improving anti-inflammatory response and facilitating macrophage reversed from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype. Meanwhile, the BP nanosheet underwent degradation and in-situ biomineralization, which accelerated calcium phosphate formation and enhanced osteogenesis. Based on in-vitro and in-vivo data, the 3D-printed BMGP scaffold that integrated structural and functional biomimicry exhibited desirable inflammatory inhibition and in-situ biomineralization performances, as well as favorable osteogenic effect in rat critical-sized femoral bone defect. In all, such biomimetic scaffold obviously propelled bone regeneration process, and provided a promising strategy for treating critical-sized bone defects in clinic.