Porous nanomaterials (PNMs) are nanosized materials with specially designed porous structures that have been widely used in the bone tissue engineering field due to the fact of their excellent physical and chemical properties such as high porosity, high specific surface area, and ideal biodegradability. Currently, PNMs are mainly used in the following four aspects: (1) as an excellent cargo to deliver bone regenerative growth factors/drugs; (2) as a fluorescent material to trace cell differentiation and bone formation; (3) as a raw material to synthesize or modify tissue engineering scaffolds; (4) as a bio-active substance to regulate cell behavior. Recent advances in the interaction between nanomaterials and cells have revealed that autophagy, a cellular survival mechanism that regulates intracellular activity by degrading/recycling intracellular metabolites, providing energy/nutrients, clearing protein aggregates, destroying organelles, and destroying intracellular pathogens, is associated with the phagocytosis and clearance of nanomaterials as well as material-induced cell differentiation and stress. Autophagy regulates bone remodeling balance via directly participating in the differentiation of osteoclasts and osteoblasts. Moreover, autophagy can regulate bone regeneration by modulating immune cell response, thereby modulating the osteogenic microenvironment. Therefore, autophagy may serve as an effective target for nanomaterials to facilitate the bone regeneration process. Increasingly, studies have shown that PNMs can modulate autophagy to regulate bone regeneration in recent years. This paper summarizes the current advances on the main application of PNMs in bone regeneration, the critical role of autophagy in bone regeneration, and the mechanism of PNMs regulating bone regeneration by targeting autophagy.

Hydrogels have been widely applied to the fabrication of tissue engineering scaffolds via three-dimensional (3D) bioprinting because of their extracellular matrix-like properties, capacity for living cell encapsulation, and shapeable customization depending on the defect shape. However, the current hydrogel scaffolds show limited regeneration activity, especially in the application of periodontal tissue regeneration. In this study, we attempted to develop a novel multi-component hydrogel that possesses good biological activity, can wrap living cells for 3D bioprinting and can regenerate periodontal soft and hard tissue. The multi-component hydrogel consisted of gelatin methacryloyl (GelMA), sodium alginate (SA) and bioactive glass microsphere (BGM), which was first processed into hydrogel scaffolds by cell-free 3D printing to evaluate its printability and in vitro biological performances. The cell-free 3D-printed scaffolds showed uniform porous structures and good swelling capability. The BGM-loaded scaffold exhibited good biocompatibility, enhanced osteogenic differentiation, apatite formation abilities and desired mechanical strength. The composite hydrogel was further applied as a bio-ink to load with mouse bone marrow mesenchymal stem cells (mBMSCs) and growth factors (BMP2 and PDGF) for the fabrication of a scaffold for periodontal tissue regeneration. The cell wrapped in the hydrogel still maintained good cellular vitality after 3D bioprinting and showed enhanced osteogenic differentiation and soft tissue repair capabilities in BMP2- and PDGF-loaded scaffolds. It was noted that after transplantation of the cell- and growth factor-laden scaffolds in Beagle dog periodontal defects, significant regeneration of gingival tissue, periodontal ligament, and alveolar bone was detected. Importantly, a reconstructed periodontal structure was established in the treatment group eight weeks post-transplantation of the scaffolds containing the cell and growth factors. In conclusion, we developed a bioactive composite bio-ink for the fabrication of scaffolds applicable for the reconstruction and regeneration of periodontal tissue defects.