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.

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.

Apoptotic bodies (ABs) are extracellular vesicles released during apoptosis and possess diverse biological activities. Initially, ABs were regarded as garbage bags with the main function of apoptotic cell clearance. Recent research has found that ABs carry and deliver various biological agents and are taken by surrounding and distant cells, affecting cell functions and behavior. ABs-mediated intercellular communications are involved in various physiological processes including anti-inflammation and tissue regeneration as well as the pathogenesis of a variety of diseases including cancer, cardiovascular diseases, neurodegeneration, and inflammatory diseases. ABs in biological fluids can be used as a window of altered cellular and tissue states which can be applied in the diagnosis and prognosis of various diseases. The structural and constituent versatility of ABs provides flexibility for tailoring ABs according to disease diagnostic and therapeutic needs. An in-depth understanding of ABs’ constituents and biological functions is mandatory for the effective tailoring of ABs including modification of bio membrane and cargo constituents. ABs’ tailoring approaches including physical, chemical, biological, and genetic have been proposed for bench-to-bed translation in disease diagnosis, prognosis, and therapy. This review summarizes the updates on ABs tailoring approaches, discusses the existing challenges, and speculates the prospects for effective diagnostic and therapeutic applications.

Nanomaterial-mediated macrophage immune response plays a crucial role in bone regeneration microenvironment. Mesoporous silica nanoparticles are widely used as nano-drug carriers, imaging agents, and bioactivity regulators for potential tissue regeneration. It is known that surface topography features of nanomaterials play an important regulatory role in the immune response. In this study, it was found that the pollen-like surface morphology of mesoporous silica nanoparticles (PMSNs) inhibited the expression of pro-inflammatory markers at gene and protein levels in macrophages (RAW 264.7 cells) compared to the smooth surface morphology of mesoporous silica nanoparticles (MSNs). Scanning electron microscopy images showed distinct macrophage membrane surface binding patterns of MSNs and PMSNs. MSNs were more evenly dispersed across the macrophage cell membrane, while PMSNs were aggregated on the membrane and prevented the M1 polarization of macrophages. PMSNs-induced macrophage anti-inflammatory responses were associated with up-regulation of the cell surface receptor CD28 and inhibition of ERK phosphorylation. TEM images showed that macrophages phagocytosed both MSNs and PMSNs while inhibiting nanoparticle phagocytosis did not affect the expression of anti-inflammatory genes and proteins. Moreover, PMSNs-induced conditioned medium from macrophages promoted osteogenic differentiation of mouse bone marrow-derived stromal cells (mBMSCs), evidenced by increased mineralization and osteogenic marker BMP2 expression via Alizarin Red S and LSCM assays compared to MSNs-induced conditioned medium. Moreover, a lipopolysaccharide (LPS)-induced osteolysis model in mouse cranial bone further demonstrated that PMSNs prevent bone resorption by mitigating LPS-induced inflammation. Our results revealed that PMSNs-mediated macrophage immunomodulation promotes bone regeneration via surface topology-related physical contact cues. STATEMENT OF SIGNIFICANCE: Nanomaterials have been widely used in bone regeneration. The immune response of macrophages induced by nanomaterials, plays a crucial role in bone regeneration. However, most nanomaterial immunomodulatory research focus on macrophage internalization or phagocytosis. The early contact between the cell membrane and nanomaterials is often easily overlooked. To clarify how early contact between nanomaterial-cell membrane regulates macrophage immune response. We developed MSN particles with special pollen-like surface morphology and studied the impact of nanoparticle morphology on the early contact between materials and macrophage cell membranes, as well as the subsequent impact on macrophage immune response and bone regeneration and related regulatory mechanisms. The results can provide new guidance for the design and development of osteoimmunomodulatory nanomaterials.

Bone defect treatment remains a significant clinical challenge, further exacerbated by the demographic transition toward an aging society. In elderly populations, the increased proportion of senescent cells emerges as a fundamental determinant that substantially compromises regenerative outcomes. In senescent bone tissues, the progressive accumulation of senescent cells compromises bone regenerative capacity through multifaceted mechanisms, encompassing both intrinsic functional impairment of senescent cells and the far-reaching impact of the senescence-associated secretory phenotype (SASP) on the surrounding cellular and tissue microenvironment. Advanced biomaterials provide a platform for targeted anti-senescence interventions. One strategy is the selective elimination of senescent cells, achieved by engineering materials as delivery systems for senolytics or as platforms that modulate immune clearance. A more nuanced approach seeks functional rejuvenation, using biomaterials to restore cellular homeostasis by mitigating inflammation, correcting metabolic dysfunction, and reprogramming gene expression. A holistic strategy remodels the senescent microenvironment itself, accomplished through materials designed to restore biochemical homeostasis, provide physical guidance, and reprogram biological communication. This review delineates these material-based strategies, from direct cellular targeting to comprehensive niche remodeling. We also evaluate the significant hurdles to clinical translation, including challenges in biological specificity, preclinical model fidelity, and regulatory pathways. Ultimately, this work provides a conceptual framework for designing next-generation biomaterials to regenerate aging bone tissues.

Objective: Current laboratory studies on the effect of biomaterial properties on immune reactions are incomplete and based on a single or a few combination features of the biomaterial design. This study utilizes intelligent prediction models to explore the key features of titanium implant materials in macrophage polarization. Impact Statement: This pilot study provided some insights into the great potential of machine learning in exploring bone immunomodulatory biomaterials. Introduction: Titanium materials are commonly utilized as bone replacement materials to treat missing teeth and bone defects. The immune response caused by implant materials after implantation in the body has a double-edged sword effect on osseointegration. Macrophage polarization has been extensively explored to understand early material-mediated immunomodulation. However, understanding of implant material surface properties and immunoregulations remains limited due to current experimental settings, which are based on trial-by-trial approaches. Artificial intelligence, with its capacity to analyze large datasets, can help explore complex material–cell interactions. Methods: In this study, the effect of titanium surface properties on macrophage polarization was analyzed using intelligent prediction models, including random forest, extreme gradient boosting, and multilayer perceptron. Additionally, data extracted from the newly published literature were further input into the trained models to validate their performance. Results: The analysis identified “cell seeding density”, “contact angle”, and “roughness” as the most important features regulating interleukin 10 and tumor necrosis factor α secretion. Additionally, the predicted interleukin 10 levels closely matched the experimental results from newly published literature, while the tumor necrosis factor α predictions exhibited consistent trends. Conclusion: The polarization response of macrophages seeded on titanium materials is influenced by multiple factors, and artificial intelligence can assist in extracting the key features of implant materials for immunoregulation.