The role of neutrophils in bone regeneration remains elusive. In this study, it is shown that intramuscular implantation of interleukin-8 (IL-8) (commonly recognized as a chemotactic cytokine for neutrophils) at different levels lead to outcomes resembling those of fracture hematoma at various stages. Ectopic endochondral ossification is induced by certain levels of IL-8, during which neutrophils are recruited to the implanted site and are N2-polarized, which then secrete stromal cell-derived factor-1α (SDF-1α) for bone mesenchymal stem cell (BMSC) chemotaxis via the SDF-1/CXCR4 (C-X-C motif chemokine receptor 4) axis and its downstream phosphatidylinositol 3'-kinase (PI3K)/Akt pathway and β-catenin-mediated migration. Neutrophils are pivotal for recruiting and orchestrating innate and adaptive immunocytes, as well as BMSCs at the initial stage of bone healing and regeneration. The results in this study delineate the mechanism of neutrophil-initiated bone regeneration and interaction between neutrophils and BMSCs, and innate and adaptive immunities. This work lays the foundation for research in the fields of bone regenerative therapy and biomaterial development, and might inspire further research into novel therapeutic options.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/advs.202100584

N2-Polarized Neutrophils Guide Bone Mesenchymal Stem Cell Recruitment and Initiate Bone Regeneration: A Missing Piece of the Bone Regeneration Puzzle.

Large-sized bone defects are a great challenge in clinics and considerably impair the quality of patients' daily life. Tissue engineering strategies using cells, scaffolds, and bioactive molecules to regulate the microenvironment in bone regeneration is a promising approach. Zinc, magnesium, and iron ions are natural elements in bone tissue and participate in many physiological processes of bone metabolism and therefore have great potential for bone tissue engineering and regeneration. In this review, we performed a systematic analysis on the effects of zinc, magnesium, and iron ions in bone tissue engineering. We focus on the role of these ions in properties of scaffolds (mechanical strength, degradation, osteogenesis, antibacterial properties, etc.). We hope that our summary of the current research achievements and our notifications of potential strategies to improve the effects of zinc, magnesium, and iron ions in scaffolds for bone repair and regeneration will find new inspiration and breakthroughs to inspire future research.

Effects of Zinc, Magnesium, and Iron Ions on Bone Tissue Engineering.

Titanium implants have been widely applied in dentistry and orthopedics due to their biocompatibility and resistance to mechanical fatigue. TiO2 nanotube arrays (TiO2 NTAs) on titanium implant surfaces have exhibited excellent biocompatibility, bioactivity, and adjustability, which can significantly promote osseointegration and participate in its entire path. In this review, to give a comprehensive understanding of the osseointegration process, four stages have been divided according to pivotal biological processes, including protein adsorption, inflammatory cell adhesion/inflammatory response, additional relevant cell adhesion and angiogenesis/osteogenesis. The impact of TiO2 NTAs on osseointegration is clarified in detail from the four stages. The nanotubular layer can manipulate the quantity, the species and the conformation of adsorbed protein. For inflammatory cells adhesion and inflammatory response, TiO2 NTAs improve macrophage adhesion on the surface and induce M2-polarization. TiO2 NTAs also facilitate the repairment-related cells adhesion and filopodia formation for additional relevant cells adhesion. In the angiogenesis and osteogenesis stage, TiO2 NTAs show the ability to induce osteogenic differentiation and the potential for blood vessel formation. In the end, we propose the multi-dimensional regulation of TiO2 NTAs on titanium implants to achieve highly efficient manipulation of osseointegration, which may provide views on the rational design and development of titanium implants. 

Nanostructured Titanium Implant Surface Facilitating Osseointegration from Protein Adsorption to Osteogenesis: The Example of TiO2 NTAs

Activated macrophage membrane-coated nanoparticles relieve osteoarthritis-induced synovitis and joint damage.

The immune response of the host towards foreign body, especially in the form of giant cell reaction against the implanted materials, is a vital factor for determining the repair outcome of bone defect. Biomaterials with good immunomodulatory capacity and suitable degradation may promote the regeneration of bone defect and osteointegration with the host. Small intestine submucosa (SIS), a decellularized material, has been shown to possess a property for inducing the M2 phenotype of macrophages. Our findings suggested that the SIS hydrogel could induce the macrophages to polarize into mixed M1/M2 phenotypes, and such phenotypes have enhanced the migration and tube formation of angiogenesis-associated cells in vitro , whilst having a mild effect on osteoclastogenesis and osteogenesis. Experiment with a rat model for critical-sized bone defect regeneration further demonstrated that the composite BMP-2@SIS hydrogel could sequentially activate M1 and M2 macrophages and promote early-stage angiogenesis, which altogether expedited final bone defect regeneration. 

Accelerated bone defect regeneration through sequential activation of the M1 and M2 phenotypes of macrophages by a composite BMP-2@SIS hydrogel: An immunomodulatory perspective

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N2-Polarized Neutrophils Guide Bone Mesenchymal Stem Cell Recruitment and Initiate Bone Regeneration: A Missing Piece of the Bone Regeneration Puzzle.