Implants are essential therapeutic tools for treating bone fractures and joint replacements. Despite the in-depth study of osseointegration for more than fifty years, poor osseointegration caused by aseptic loosening remains one of the leading causes of late implant failures. Osseointegration is a highly sophisticated and spatiotemporal process in vivo involving the immune response, angiogenesis, and osteogenesis. It has been unraveled that the nervous system plays a pivotal role in skeletal health via manipulating neurotrophins, neuropeptides, and nerve cells. Herein, the research related to nervous system-driven osseointegration was systematically analyzed and reviewed, aiming to demonstrate the prominent role of neuromodulation in osseointegration. Additionally, it is indicated that the implant design considering the role of neuromodulation might be a promising way to prevent aseptic loosening.

Despite the high success rate of biomedical implants adopted clinically, implant failures caused by aseptic loosening still raise the risk of secondary surgery and a substantial economic burden to patients. Improving the stable combination between the implant and the host bone tissue, achieving fast and high-quality osseointegration can effectively reduce the probability of aseptic loosening. Accumulating studies have shown that the osteoimmunomodulation mediated by immune cells mainly dominated by macrophages plays a pivotal role in osseointegration by releasing active factors to improve the inflammatory microenvironment. However, the mechanism by which osteoimmunomodulation mediates osseointegration remains unclear. Recent studies have revealed that exosomes released by macrophages play a central role in mediating osteoimmunomodulation. The exosomes can be internalized by various cells participating in de novo bone formation, such as endothelial cells and osteoblasts, to intervene in the osseointegration robustly. Therefore, macrophage-derived exosomes with multifunctionality are expected to significantly improve the osseointegration microenvironment, which is promising in reducing the occurrence of aseptic loosening. Based on this, this review summarizes recent studies on the effects of exosomes derived from the immune cells on osseointegration, aiming to provide a theoretical foundation for improving the clinical success rate of biomedical implants and achieving high-quality and high-efficiency osseointegration.

Bone marrow mesenchymal stem cells (BMSCs) have self-renewal, multi-directional differentiation potential, and immune regulation function and are widely used for de novo bone formation. However, the wide variation in individual amplification, the potential risk of cancer cell contamination, and the need for culture time significantly limit their widespread use clinically. Alternatively, numerous studies have shown that exosomes secreted by BMSCs in the nanoscale can also affect the functionality of endothelial cells (angiogenesis), macrophages (immunomodulation), and osteoblasts/osteoclasts (osteogenesis), which is a highly promising therapy for osseointegration with pronounced advantages (e.g., safety, high efficiency, and no ethical restrictions). The review aims to summarize the multifaceted effect of BMSCs-derived exosomes on osseointegration and provide reference and basis for rapid and qualified osseointegration.