Is there a role for N1-N2 neutrophil phenotypes in bone regeneration? A systematic review

Purpose: This review aims to provide an overview of the multiple functions of neutrophils, with the recognition of the inflammatory (N1) and regenerative (N2) phenotypes, in relation to fracture healing. Methods: A literature search was performed using the PubMed database. The quality of the articles was evaluated using critical appraisal checklists. Results: Thirty one studies were included in this review. These studies consistently support that neutrophils exert both beneficial and detrimental effects on bone regeneration, influenced by Tumor Necrosis Factor-alpha (TNF-alpha), Interleukin 8 (IL-8), mast cells, and macrophages. The N2 phenotype has recently emerged as one promoter of bone healing. The N1 phenotype has progressively been connected with inflammatory neutrophils during fracture healing. Conclusions: This review has pinpointed various aspects and mechanisms of neutrophil influence on bone healing. The recognition of N1 and N2 neutrophil phenotypes potentially shed new light on the dynamic shifts taking place within the Fracture Hematoma (FH).